bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒09‒03
58 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The cost of being a student.
  2. Transposable elements as tissue-specific enhancers in cancers of endodermal lineage.
  3. Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
  4. Phage-assisted evolution and protein engineering yield compact, efficient prime editors.
  5. Downregulation of transposable elements extends lifespan in Caenorhabditis elegans.
  6. CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.
  7. Metabolic programs of T cell tissue residency empower tumour immunity.
  8. Previously unknown pathway for lipid biosynthesis discovered.
  9. High-resolution landscape of an antibiotic binding site.
  10. Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.
  11. Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype.
  12. Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.
  13. Did our ancestors nearly die out?
  14. Engaging an HIV vaccine target through the acquisition of low B cell affinity.
  15. Acetylcholine modulates the temporal dynamics of human theta oscillations during memory.
  16. Barcoded multiple displacement amplification for high coverage sequencing in spatial genomics.
  17. Donald Brown (1931-2023).
  18. Control of murine brown adipocyte development by GATA6.
  19. Identification of an alternative triglyceride biosynthesis pathway.
  20. Deep and fast label-free Dynamic Organellar Mapping.
  21. DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability.
  22. AI excels at name that smell.
  23. Using a synthetic machinery to improve carbon yield with acetylphosphate as the core.
  24. Next generation synthetic memory via intercepting recombinase function.
  25. Sex differences in brain protein expression and disease.
  26. p16High senescence restricts cellular plasticity during somatic cell reprogramming.
  27. Portosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry.
  28. A portable regulatory RNA array design enables tunable and complex regulation across diverse bacteria.
  29. The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.
  30. Reconstructing human brown fat developmental trajectory in vitro.
  31. Biomarkers of aging for the identification and evaluation of longevity interventions.
  32. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.
  33. Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies.
  34. Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.
  35. ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2.
  36. PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
  37. Leading basic modes of spontaneous activity drive individual functional connectivity organization in the resting human brain.
  38. Dynamically regulated two-site interaction of viral RNA to capture host translation initiation factor.
  39. Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling.
  40. Interrogating the viral dark matter of the rumen ecosystem with a global virome database.
  41. scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.
  42. Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation.
  43. Practical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests.
  44. Strike at outbreak-alert service ProMED to end - but tensions remain.
  45. Neutralization, effector function and immune imprinting of Omicron variants.
  46. Targeted mechanical stimulation via magnetic nanoparticles guides in vitro tissue development.
  47. A non-coding m6A reader promotes leukaemia.
  48. Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection.
  49. Hydroxytryptophan biosynthesis by a family of heme-dependent enzymes in bacteria.
  50. Delayed gut microbiota maturation in the first year of life is a hallmark of pediatric allergic disease.
  51. CODEX multiplexed tissue imaging.
  52. Unanswered questions about the causes of obesity.
  53. CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications.
  54. RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.
  55. A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.
  56. Human ancestors nearly went extinct 900,000 years ago.
  57. Critical dynamics arise during structured information presentation within embodied in vitro neuronal networks.
  58. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
  1. Science. 2023 Sep;381(6661): 1018
    The cost of being a student.
    Faye Harwell.
      
    DOI:  https://doi.org/10.1126/science.adk5091
  2. Nat Commun. 2023 Sep 01. 14(1): 5313
    Transposable elements as tissue-specific enhancers in cancers of endodermal lineage.
    Konsta Karttunen, Divyesh Patel, Jihan Xia, Liangru Fei, Kimmo Palin, Lauri Aaltonen, Biswajyoti Sahu.
      Transposable elements (TE) are repetitive genomic elements that harbor binding sites for human transcription factors (TF). A regulatory role for TEs has been suggested in embryonal development and diseases such as cancer but systematic investigation of their functions has been limited by their widespread silencing in the genome. Here, we utilize unbiased massively parallel reporter assay data using a whole human genome library to identify TEs with functional enhancer activity in two human cancer types of endodermal lineage, colorectal and liver cancers. We show that the identified TE enhancers are characterized by genomic features associated with active enhancers, such as epigenetic marks and TF binding. Importantly, we identify distinct TE subfamilies that function as tissue-specific enhancers, namely MER11- and LTR12-elements in colon and liver cancers, respectively. These elements are bound by distinct TFs in each cell type, and they have predicted associations to differentially expressed genes. In conclusion, these data demonstrate how different cancer types can utilize distinct TEs as tissue-specific enhancers, paving the way for comprehensive understanding of the role of TEs as bona fide enhancers in the cancer genomes.
    DOI:  https://doi.org/10.1038/s41467-023-41081-4
  3. Nat Commun. 2023 Aug 28. 14(1): 5241
    Structural basis of HIV-1 Vif-mediated E3 ligase targeting of host APOBEC3H.
    Fumiaki Ito, Ana L Alvarez-Cabrera, Kyumin Kim, Z Hong Zhou, Xiaojiang S Chen.
      Human APOBEC3 (A3) cytidine deaminases are antiviral factors that are particularly potent against retroviruses. As a countermeasure, HIV-1 uses a viral infectivity factor (Vif) to target specific human A3s for proteasomal degradation. Vif recruits cellular transcription cofactor CBF-β and Cullin-5 (CUL5) RING E3 ubiquitin ligase to bind different A3s distinctively, but how this is accomplished remains unclear in the absence of the atomic structure of the complex. Here, we present the cryo-EM structures of HIV-1 Vif in complex with human A3H, CBF-β and components of CUL5 ubiquitin ligase (CUL5, ELOB, and ELOC). Vif nucleates the entire complex by directly binding four human proteins, A3H, CBF-β, CUL5, and ELOC. The structures reveal a large interface area between A3H and Vif, primarily mediated by an α-helical side of A3H and a five-stranded β-sheet of Vif. This A3H-Vif interface unveils the basis for sensitivity-modulating polymorphism of both proteins, including a previously reported gain-of-function mutation in Vif isolated from HIV/AIDS patients. Our structural and functional results provide insights into the remarkable interplay between HIV and humans and would inform development efforts for anti-HIV therapeutics.
    DOI:  https://doi.org/10.1038/s41467-023-40955-x
  4. Cell. 2023 Aug 31. pii: S0092-8674(23)00854-1. [Epub ahead of print]186(18): 3983-4002.e26
    Phage-assisted evolution and protein engineering yield compact, efficient prime editors.
    Jordan L Doman, Smriti Pandey, Monica E Neugebauer, Meirui An, Jessie R Davis, Peyton B Randolph, Amber McElroy, Xin D Gao, Aditya Raguram, Michelle F Richter, Kelcee A Everette, Samagya Banskota, Kathryn Tian, Y Allen Tao, Jakub Tolar, Mark J Osborn, David R Liu.
      Prime editing enables a wide variety of precise genome edits in living cells. Here we use protein evolution and engineering to generate prime editors with reduced size and improved efficiency. Using phage-assisted evolution, we improved editing efficiencies of compact reverse transcriptases by up to 22-fold and generated prime editors that are 516-810 base pairs smaller than the current-generation editor PEmax. We discovered that different reverse transcriptases specialize in different types of edits and used this insight to generate reverse transcriptases that outperform PEmax and PEmaxΔRNaseH, the truncated editor used in dual-AAV delivery systems. Finally, we generated Cas9 domains that improve prime editing. These resulting editors (PE6a-g) enhance therapeutically relevant editing in patient-derived fibroblasts and primary human T-cells. PE6 variants also enable longer insertions to be installed in vivo following dual-AAV delivery, achieving 40% loxP insertion in the cortex of the murine brain, a 24-fold improvement compared to previous state-of-the-art prime editors.
    Keywords:  CRISPR-Cas9; directed evolution; genome editing; guide RNAs; pegRNAs; phage-assisted continuous evolution; prime editing; protein engineering
    DOI:  https://doi.org/10.1016/j.cell.2023.07.039
  5. Nat Commun. 2023 Aug 29. 14(1): 5278
    Downregulation of transposable elements extends lifespan in Caenorhabditis elegans.
    Ádám Sturm, Éva Saskői, Bernadette Hotzi, Anna Tarnóci, János Barna, Ferenc Bodnár, Himani Sharma, Tibor Kovács, Eszter Ari, Nóra Weinhardt, Csaba Kerepesi, András Perczel, Zoltán Ivics, Tibor Vellai.
      Mobility of transposable elements (TEs) frequently leads to insertional mutations in functional DNA regions. In the potentially immortal germline, TEs are effectively suppressed by the Piwi-piRNA pathway. However, in the genomes of ageing somatic cells lacking the effects of the pathway, TEs become increasingly mobile during the adult lifespan, and their activity is associated with genomic instability. Whether the progressively increasing mobilization of TEs is a cause or a consequence of ageing remains a fundamental problem in biology. Here we show that in the nematode Caenorhabditis elegans, the downregulation of active TE families extends lifespan. Ectopic activation of Piwi proteins in the soma also promotes longevity. Furthermore, DNA N6-adenine methylation at TE stretches gradually rises with age, and this epigenetic modification elevates their transcription as the animal ages. These results indicate that TEs represent a novel genetic determinant of ageing, and that N6-adenine methylation plays a pivotal role in ageing control.
    DOI:  https://doi.org/10.1038/s41467-023-40957-9
  6. Nature. 2023 Aug 30.
    CRISPR screens decode cancer cell pathways that trigger γδ T cell detection.
    Murad R Mamedov, Shane Vedova, Jacob W Freimer, Avinash Das Sahu, Amrita Ramesh, Maya M Arce, Angelo D Meringa, Mineto Ota, Peixin Amy Chen, Kristina Hanspers, Vinh Q Nguyen, Kirsten A Takeshima, Anne C Rios, Jonathan K Pritchard, Jürgen Kuball, Zsolt Sebestyen, Erin J Adams, Alexander Marson.
      γδ T cells are potent anticancer effectors with the potential to target tumours broadly, independent of patient-specific neoantigens or human leukocyte antigen background1-5. γδ T cells can sense conserved cell stress signals prevalent in transformed cells2,3, although the mechanisms behind the targeting of stressed target cells remain poorly characterized. Vγ9Vδ2 T cells-the most abundant subset of human γδ T cells4-recognize a protein complex containing butyrophilin 2A1 (BTN2A1) and BTN3A1 (refs. 6-8), a widely expressed cell surface protein that is activated by phosphoantigens abundantly produced by tumour cells. Here we combined genome-wide CRISPR screens in target cancer cells to identify pathways that regulate γδ T cell killing and BTN3A cell surface expression. The screens showed previously unappreciated multilayered regulation of BTN3A abundance on the cell surface and triggering of γδ T cells through transcription, post-translational modifications and membrane trafficking. In addition, diverse genetic perturbations and inhibitors disrupting metabolic pathways in the cancer cells, particularly ATP-producing processes, were found to alter BTN3A levels. This induction of both BTN3A and BTN2A1 during metabolic crises is dependent on AMP-activated protein kinase (AMPK). Finally, small-molecule activation of AMPK in a cell line model and in patient-derived tumour organoids led to increased expression of the BTN2A1-BTN3A complex and increased Vγ9Vδ2 T cell receptor-mediated killing. This AMPK-dependent mechanism of metabolic stress-induced ligand upregulation deepens our understanding of γδ T cell stress surveillance and suggests new avenues available to enhance γδ T cell anticancer activity.
    DOI:  https://doi.org/10.1038/s41586-023-06482-x
  7. Nature. 2023 Aug 30.
    Metabolic programs of T cell tissue residency empower tumour immunity.
    Miguel Reina-Campos, Maximilian Heeg, Kelly Kennewick, Ian T Mathews, Giovanni Galletti, Vida Luna, Quynhanh Nguyen, Hongling Huang, J Justin Milner, Kenneth H Hu, Amy Vichaidit, Natalie Santillano, Brigid S Boland, John T Chang, Mohit Jain, Sonia Sharma, Matthew F Krummel, Hongbo Chi, Steven J Bensinger, Ananda W Goldrath.
      Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.
    DOI:  https://doi.org/10.1038/s41586-023-06483-w
  8. Nature. 2023 Sep;621(7977): 47-48
    Previously unknown pathway for lipid biosynthesis discovered.
    Jean E Schaffer.
      
    Keywords:  Biochemistry; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-02502-y
  9. Nature. 2023 Aug 30.
    High-resolution landscape of an antibiotic binding site.
    Kevin B Yang, Maria Cameranesi, Manjunath Gowder, Criseyda Martinez, Yosef Shamovsky, Vitaliy Epshtein, Zhitai Hao, Thao Nguyen, Eric Nirenstein, Ilya Shamovsky, Aviram Rasouly, Evgeny Nudler.
      Antibiotic binding sites are located in important domains of essential enzymes and have been extensively studied in the context of resistance mutations; however, their study is limited by positive selection. Using multiplex genome engineering1 to overcome this constraint, we generate and characterize a collection of 760 single-residue mutants encompassing the entire rifampicin binding site of Escherichia coli RNA polymerase (RNAP). By genetically mapping drug-enzyme interactions, we identify an alpha helix where mutations considerably enhance or disrupt rifampicin binding. We find mutations in this region that prolong antibiotic binding, converting rifampicin from a bacteriostatic to bactericidal drug by inducing lethal DNA breaks. The latter are replication dependent, indicating that rifampicin kills by causing detrimental transcription-replication conflicts at promoters. We also identify additional binding site mutations that greatly increase the speed of RNAP.Fast RNAP depletes the cell of nucleotides, alters cell sensitivity to different antibiotics and provides a cold growth advantage. Finally, by mapping natural rpoB sequence diversity, we discover that functional rifampicin binding site mutations that alter RNAP properties or confer drug resistance occur frequently in nature.
    DOI:  https://doi.org/10.1038/s41586-023-06495-6
  10. Nat Biotechnol. 2023 Aug 28.
    Joint single-cell profiling resolves 5mC and 5hmC and reveals their distinct gene regulatory effects.
    Emily B Fabyanic, Peng Hu, Qi Qiu, Kiara N Berríos, Daniel R Connolly, Tong Wang, Jennifer Flournoy, Zhaolan Zhou, Rahul M Kohli, Hao Wu.
      Oxidative modification of 5-methylcytosine (5mC) by ten-eleven translocation (TET) DNA dioxygenases generates 5-hydroxymethylcytosine (5hmC), the most abundant form of oxidized 5mC. Existing single-cell bisulfite sequencing methods cannot resolve 5mC and 5hmC, leaving the cell-type-specific regulatory mechanisms of TET and 5hmC largely unknown. Here, we present joint single-nucleus (hydroxy)methylcytosine sequencing (Joint-snhmC-seq), a scalable and quantitative approach that simultaneously profiles 5hmC and true 5mC in single cells by harnessing differential deaminase activity of APOBEC3A toward 5mC and chemically protected 5hmC. Joint-snhmC-seq profiling of single nuclei from mouse brains reveals an unprecedented level of epigenetic heterogeneity of both 5hmC and true 5mC at single-cell resolution. We show that cell-type-specific profiles of 5hmC or true 5mC improve multimodal single-cell data integration, enable accurate identification of neuronal subtypes and uncover context-specific regulatory effects on cell-type-specific genes by TET enzymes.
    DOI:  https://doi.org/10.1038/s41587-023-01909-2
  11. Nat Commun. 2023 Aug 26. 14(1): 5226
    Coordinated single-cell tumor microenvironment dynamics reinforce pancreatic cancer subtype.
    Ki Oh, Yun Jae Yoo, Luke A Torre-Healy, Manisha Rao, Danielle Fassler, Pei Wang, Michael Caponegro, Mei Gao, Joseph Kim, Aaron Sasson, Georgios Georgakis, Scott Powers, Richard A Moffitt.
      Bulk analyses of pancreatic ductal adenocarcinoma (PDAC) samples are complicated by the tumor microenvironment (TME), i.e. signals from fibroblasts, endocrine, exocrine, and immune cells. Despite this, we and others have established tumor and stroma subtypes with prognostic significance. However, understanding of underlying signals driving distinct immune and stromal landscapes is still incomplete. Here we integrate 92 single cell RNA-seq samples from seven independent studies to build a reproducible PDAC atlas with a focus on tumor-TME interdependence. Patients with activated stroma are synonymous with higher myofibroblastic and immunogenic fibroblasts, and furthermore show increased M2-like macrophages and regulatory T-cells. Contrastingly, patients with 'normal' stroma show M1-like recruitment, elevated effector and exhausted T-cells. To aid interoperability of future studies, we provide a pretrained cell type classifier and an atlas of subtype-based signaling factors that we also validate in mouse data. Ultimately, this work leverages the heterogeneity among single-cell studies to create a comprehensive view of the orchestra of signaling interactions governing PDAC.
    DOI:  https://doi.org/10.1038/s41467-023-40895-6
  12. Nat Metab. 2023 Aug 31.
    Hypothalamic GABRA5-positive neurons control obesity via astrocytic GABA.
    Moonsun Sa, Eun-Seon Yoo, Wuhyun Koh, Mingu Gordon Park, Hyun-Jun Jang, Yong Ryoul Yang, Mridula Bhalla, Jae-Hun Lee, Jiwoon Lim, Woojin Won, Jea Kwon, Joon-Ho Kwon, Yejin Seong, Byungeun Kim, Heeyoung An, Seung Eun Lee, Ki Duk Park, Pann-Ghill Suh, Jong-Woo Sohn, C Justin Lee.
      The lateral hypothalamic area (LHA) regulates food intake and energy balance. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we show that GABRA5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity mouse models in males. Chemogenetic inhibition of GABRA5LHA suppresses fat thermogenesis and increases weight gain, whereas gene silencing of GABRA5 in LHA decreases weight gain. In the diet-induced obesity mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by monoamine oxidase B (Maob). Gene silencing of astrocytic Maob in LHA facilitates fat thermogenesis and reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a Maob inhibitor, KDS2010. We propose that firing of GABRA5LHA suppresses fat accumulation and selective inhibition of astrocytic GABA is a molecular target for treating obesity.
    DOI:  https://doi.org/10.1038/s42255-023-00877-w
  13. Science. 2023 Sep;381(6661): 947-948
    Did our ancestors nearly die out?
    Nick Ashton, Chris Stringer.
      Genetic analyses suggest an ancient human population crash 900,000 years ago.
    DOI:  https://doi.org/10.1126/science.adj9484
  14. Nat Commun. 2023 Aug 28. 14(1): 5249
    Engaging an HIV vaccine target through the acquisition of low B cell affinity.
    Larance Ronsard, Ashraf S Yousif, Faez Amokrane Nait Mohamed, Jared Feldman, Vintus Okonkwo, Caitlin McCarthy, Julia Schnabel, Timothy Caradonna, Ralston M Barnes, Daniel Rohrer, Nils Lonberg, Aaron Schmidt, Daniel Lingwood.
      Low affinity is common for germline B cell receptors (BCR) seeding development of broadly neutralizing antibodies (bnAbs) that engage hypervariable viruses, including HIV. Antibody affinity selection is also non-homogenizing, insuring the survival of low affinity B cell clones. To explore whether this provides a natural window for expanding human B cell lineages against conserved vaccine targets, we deploy transgenic mice mimicking human antibody diversity and somatic hypermutation (SHM) and immunize with simple monomeric HIV glycoprotein envelope immunogens. We report an immunization regimen that focuses B cell memory upon the conserved CD4 binding site (CD4bs) through both conventional affinity maturation and reproducible expansion of low affinity BCR clones with public patterns in SHM. In the latter instance, SHM facilitates target acquisition by decreasing binding strength. This suggests that permissive B cell selection enables the discovery of antibody epitopes, in this case an HIV bnAb site.
    DOI:  https://doi.org/10.1038/s41467-023-40918-2
  15. Nat Commun. 2023 Aug 30. 14(1): 5283
    Acetylcholine modulates the temporal dynamics of human theta oscillations during memory.
    Tamara Gedankien, Ryan Joseph Tan, Salman Ehtesham Qasim, Haley Moore, David McDonagh, Joshua Jacobs, Bradley Lega.
      The cholinergic system is essential for memory. While degradation of cholinergic pathways characterizes memory-related disorders such as Alzheimer's disease, the neurophysiological mechanisms linking the cholinergic system to human memory remain unknown. Here, combining intracranial brain recordings with pharmacological manipulation, we describe the neurophysiological effects of a cholinergic blocker, scopolamine, on the human hippocampal formation during episodic memory. We found that the memory impairment caused by scopolamine was coupled to disruptions of both the amplitude and phase alignment of theta oscillations (2-10 Hz) during encoding. Across individuals, the severity of theta phase disruption correlated with the magnitude of memory impairment. Further, cholinergic blockade disrupted connectivity within the hippocampal formation. Our results indicate that cholinergic circuits support memory by coordinating the temporal dynamics of theta oscillations across the hippocampal formation. These findings expand our mechanistic understanding of the neurophysiology of human memory and offer insights into potential treatments for memory-related disorders.
    DOI:  https://doi.org/10.1038/s41467-023-41025-y
  16. Nat Commun. 2023 Aug 29. 14(1): 5261
    Barcoded multiple displacement amplification for high coverage sequencing in spatial genomics.
    Jinhyun Kim, Sungsik Kim, Huiran Yeom, Seo Woo Song, Kyoungseob Shin, Sangwook Bae, Han Suk Ryu, Ji Young Kim, Ahyoun Choi, Sumin Lee, Taehoon Ryu, Yeongjae Choi, Hamin Kim, Okju Kim, Yushin Jung, Namphil Kim, Wonshik Han, Han-Byoel Lee, Amos C Lee, Sunghoon Kwon.
      Determining mutational landscapes in a spatial context is essential for understanding genetically heterogeneous cell microniches. Current approaches, such as Multiple Displacement Amplification (MDA), offer high genome coverage but limited multiplexing, which hinders large-scale spatial genomic studies. Here, we introduce barcoded MDA (bMDA), a technique that achieves high-coverage genomic analysis of low-input DNA while enhancing the multiplexing capabilities. By incorporating cell barcodes during MDA, bMDA streamlines library preparation in one pot, thereby overcoming a key bottleneck in spatial genomics. We apply bMDA to the integrative spatial analysis of triple-negative breast cancer tissues by examining copy number alterations, single nucleotide variations, structural variations, and kataegis signatures for each spatial microniche. This enables the assessment of subclonal evolutionary relationships within a spatial context. Therefore, bMDA has emerged as a scalable technology with the potential to advance the field of spatial genomics significantly.
    DOI:  https://doi.org/10.1038/s41467-023-41019-w
  17. Cell. 2023 Aug 31. pii: S0092-8674(23)00810-3. [Epub ahead of print]186(18): 3745-3746
    Donald Brown (1931-2023).
    Douglas Koshland.
      
    DOI:  https://doi.org/10.1016/j.cell.2023.07.032
  18. Dev Cell. 2023 Aug 23. pii: S1534-5807(23)00399-4. [Epub ahead of print]
    Control of murine brown adipocyte development by GATA6.
    Seoyoung Jun, Anthony R Angueira, Ethan C Fein, Josephine M E Tan, Angela H Weller, Lan Cheng, Kirill Batmanov, Jeff Ishibashi, Alexander P Sakers, Rachel R Stine, Patrick Seale.
      Brown adipose tissue (BAT) is a thermogenic organ that protects animals against hypothermia and obesity. BAT derives from the multipotent paraxial mesoderm; however, the identity of embryonic brown fat progenitor cells and regulators of adipogenic commitment are unclear. Here, we performed single-cell gene expression analyses of mesenchymal cells during mouse embryogenesis with a focus on BAT development. We identified cell populations associated with the development of BAT, including Dpp4+ cells that emerge at the onset of adipogenic commitment. Immunostaining and lineage-tracing studies show that Dpp4+ cells constitute the BAT fascia and contribute minorly as adipocyte progenitors. Additionally, we identified the transcription factor GATA6 as a marker of brown adipogenic progenitor cells. Deletion of Gata6 in the brown fat lineage resulted in a striking loss of BAT. Together, these results identify progenitor and transitional cells in the brown adipose lineage and define a crucial role for GATA6 in BAT development.
    Keywords:  DPP4; EBF2; GATA6; UCP1; adipose tissue; brown adipocyte; brown adipocyte development; brown adipogenesis; progenitor
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.003
  19. Nature. 2023 Aug 30.
    Identification of an alternative triglyceride biosynthesis pathway.
    Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.
      Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.
    DOI:  https://doi.org/10.1038/s41586-023-06497-4
  20. Nat Commun. 2023 Aug 29. 14(1): 5252
    Deep and fast label-free Dynamic Organellar Mapping.
    Julia P Schessner, Vincent Albrecht, Alexandra K Davies, Pavel Sinitcyn, Georg H H Borner.
      The Dynamic Organellar Maps (DOMs) approach combines cell fractionation and shotgun-proteomics for global profiling analysis of protein subcellular localization. Here, we enhance the performance of DOMs through data-independent acquisition (DIA) mass spectrometry. DIA-DOMs achieve twice the depth of our previous workflow in the same mass spectrometry runtime, and substantially improve profiling precision and reproducibility. We leverage this gain to establish flexible map formats scaling from high-throughput analyses to extra-deep coverage. Furthermore, we introduce DOM-ABC, a powerful and user-friendly open-source software tool for analyzing profiling data. We apply DIA-DOMs to capture subcellular localization changes in response to starvation and disruption of lysosomal pH in HeLa cells, which identifies a subset of Golgi proteins that cycle through endosomes. An imaging time-course reveals different cycling patterns and confirms the quantitative predictive power of our translocation analysis. DIA-DOMs offer a superior workflow for label-free spatial proteomics as a systematic phenotype discovery tool.
    DOI:  https://doi.org/10.1038/s41467-023-41000-7
  21. Nat Commun. 2023 Aug 28. 14(1): 5246
    DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability.
    Yaping Huang, Changzheng Lu, Hanzhi Wang, Liya Gu, Yang-Xin Fu, Guo-Min Li.
      Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70's cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-023-40952-0
  22. Science. 2023 Sep;381(6661): 933-934
    AI excels at name that smell.
    Elizabeth Pennisi.
      Neural network predicts odors from chemical structures.
    DOI:  https://doi.org/10.1126/science.adk5723
  23. Nat Commun. 2023 Aug 30. 14(1): 5286
    Using a synthetic machinery to improve carbon yield with acetylphosphate as the core.
    Likun Guo, Min Liu, Yujia Bi, Qingsheng Qi, Mo Xian, Guang Zhao.
      In microbial cell factory, CO2 release during acetyl-CoA production from pyruvate significantly decreases the carbon atom economy. Here, we construct and optimize a synthetic carbon conserving pathway named as Sedoheptulose-1,7-bisphosphatase Cycle with Trifunctional PhosphoKetolase (SCTPK) in Escherichia coli. This cycle relies on a generalist phosphoketolase Xfspk and converts glucose into the stoichiometric amounts of acetylphosphate (AcP). Furthermore, genetic circuits responding to AcP positively or negatively are created. Together with SCTPK, they constitute a gene-metabolic oscillator that regulates Xfspk and enzymes converting AcP into valuable chemicals in response to intracellular AcP level autonomously, allocating metabolic flux rationally and improving the carbon atom economy of bioconversion process. Using this synthetic machinery, mevalonate is produced with a yield higher than its native theoretical yield, and the highest titer and yield of 3-hydroxypropionate via malonyl-CoA pathway are achieved. This study provides a strategy for improving the carbon yield of microbial cell factories.
    DOI:  https://doi.org/10.1038/s41467-023-41135-7
  24. Nat Commun. 2023 Aug 29. 14(1): 5255
    Next generation synthetic memory via intercepting recombinase function.
    Andrew E Short, Dowan Kim, Prasaad T Milner, Corey J Wilson.
      Here we present a technology to facilitate synthetic memory in a living system via repurposing Transcriptional Programming (i.e., our decision-making technology) parts, to regulate (intercept) recombinase function post-translation. We show that interception synthetic memory can facilitate programmable loss-of-function via site-specific deletion, programmable gain-of-function by way of site-specific inversion, and synthetic memory operations with nested Boolean logical operations. We can expand interception synthetic memory capacity more than 5-fold for a single recombinase, with reconfiguration specificity for multiple sites in parallel. Interception synthetic memory is ~10-times faster than previous generations of recombinase-based memory. We posit that the faster recombination speed of our next-generation memory technology is due to the post-translational regulation of recombinase function. This iteration of synthetic memory is complementary to decision-making via Transcriptional Programming - thus can be used to develop intelligent synthetic biological systems for myriad applications.
    DOI:  https://doi.org/10.1038/s41467-023-41043-w
  25. Nat Med. 2023 Aug 31.
    Sex differences in brain protein expression and disease.
    Aliza P Wingo, Yue Liu, Ekaterina S Gerasimov, Selina M Vattathil, Jiaqi Liu, David J Cutler, Michael P Epstein, Gabriëlla A M Blokland, Madhav Thambisetty, Juan C Troncoso, Duc M Duong, David A Bennett, Allan I Levey, Nicholas T Seyfried, Thomas S Wingo.
      Most complex human traits differ by sex, but we have limited insight into the underlying mechanisms. Here, we investigated the influence of biological sex on protein expression and its genetic regulation in 1,277 human brain proteomes. We found that 13.2% (1,354) of brain proteins had sex-differentiated abundance and 1.5% (150) of proteins had sex-biased protein quantitative trait loci (sb-pQTLs). Among genes with sex-biased expression, we found 67% concordance between sex-differentiated protein and transcript levels; however, sex effects on the genetic regulation of expression were more evident at the protein level. Considering 24 psychiatric, neurologic and brain morphologic traits, we found that an average of 25% of their putatively causal genes had sex-differentiated protein abundance and 12 putatively causal proteins had sb-pQTLs. Furthermore, integrating sex-specific pQTLs with sex-stratified genome-wide association studies of six psychiatric and neurologic conditions, we uncovered another 23 proteins contributing to these traits in one sex but not the other. Together, these findings begin to provide insights into mechanisms underlying sex differences in brain protein expression and disease.
    DOI:  https://doi.org/10.1038/s41591-023-02509-y
  26. Nat Cell Biol. 2023 Aug 31.
    p16High senescence restricts cellular plasticity during somatic cell reprogramming.
    Bogdan B Grigorash, Dominic van Essen, Guixian Liang, Laurent Grosse, Alexander Emelyanov, Zhixin Kang, Alexey Korablev, Benoît Kanzler, Clement Molina, Elsa Lopez, Oleg N Demidov, Carmen Garrido, Feng Liu, Simona Saccani, Dmitry V Bulavin.
      Despite advances in four-factor (4F)-induced reprogramming (4FR) in vitro and in vivo, how 4FR interconnects with senescence remains largely under investigated. Here, using genetic and chemical approaches to manipulate senescent cells, we show that removal of p16High cells resulted in the 4FR of somatic cells into totipotent-like stem cells. These cells expressed markers of both pluripotency and the two-cell embryonic state, readily formed implantation-competent blastoids and, following morula aggregation, contributed to embryonic and extraembryonic lineages. We identified senescence-dependent regulation of nicotinamide N-methyltransferase as a key mechanism controlling the S-adenosyl-L-methionine levels during 4FR that was required for expression of the two-cell genes and acquisition of an extraembryonic potential. Importantly, a partial 4F epigenetic reprogramming in old mice was able to reverse several markers of liver aging only in conjunction with the depletion of p16High cells. Our results show that the presence of p16High senescent cells limits cell plasticity, whereas their depletion can promote a totipotent-like state and histopathological tissue rejuvenation during 4F reprogramming.
    DOI:  https://doi.org/10.1038/s41556-023-01214-9
  27. Nat Commun. 2023 Aug 31. 14(1): 5303
    Portosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry.
    Ana Carolina Dantas Machado, Stephany Flores Ramos, Julia M Gauglitz, Anne-Marie Fassler, Daniel Petras, Alexander A Aksenov, Un Bi Kim, Michael Lazarowicz, Abbey Barnard Giustini, Hamed Aryafar, Irine Vodkin, Curtis Warren, Pieter C Dorrestein, Ali Zarrinpar, Amir Zarrinpar.
      Elective transjugular intrahepatic portosystemic shunt (TIPS) placement can worsen cognitive dysfunction in hepatic encephalopathy (HE) patients due to toxins, including possible microbial metabolites, entering the systemic circulation. We conducted untargeted metabolomics on a prospective cohort of 22 patients with cirrhosis undergoing elective TIPS placement and followed them up to one year post TIPS for HE development. Here we suggest that pre-existing intrahepatic shunting predicts HE severity post-TIPS. Bile acid levels decrease in the peripheral vein post-TIPS, and the abundances of three specific conjugated di- and tri-hydroxylated bile acids are inversely correlated with HE grade. Bilirubins and glycerophosphocholines undergo chemical modifications pre- to post-TIPS and based on HE grade. Our results suggest that TIPS-induced metabolome changes can impact HE development, and that pre-existing intrahepatic shunting could be used to predict HE severity post-TIPS.
    DOI:  https://doi.org/10.1038/s41467-023-40741-9
  28. Nat Commun. 2023 Aug 29. 14(1): 5268
    A portable regulatory RNA array design enables tunable and complex regulation across diverse bacteria.
    Baiyang Liu, Christian Cuba Samaniego, Matthew R Bennett, Elisa Franco, James Chappell.
      A lack of composable and tunable gene regulators has hindered efforts to engineer non-model bacteria and consortia. Toward addressing this, we explore the broad-host potential of small transcription activating RNA (STAR) and propose a design strategy to achieve tunable gene control. First, we demonstrate that STARs optimized for E. coli function across different Gram-negative species and can actuate using phage RNA polymerase, suggesting that RNA systems acting at the level of transcription are portable. Second, we explore an RNA design strategy that uses arrays of tandem and transcriptionally fused RNA regulators to precisely alter regulator concentration from 1 to 8 copies. This provides a simple means to predictably tune output gain across species and does not require access to large regulatory part libraries. Finally, we show RNA arrays can be used to achieve tunable cascading and multiplexing circuits across species, analogous to the motifs used in artificial neural networks.
    DOI:  https://doi.org/10.1038/s41467-023-40785-x
  29. Nat Commun. 2023 Sep 01. 14(1): 5329
    The interplay between dietary fatty acids and gut microbiota influences host metabolism and hepatic steatosis.
    Marc Schoeler, Sandrine Ellero-Simatos, Till Birkner, Jordi Mayneris-Perxachs, Lisa Olsson, Harald Brolin, Ulrike Loeber, Jamie D Kraft, Arnaud Polizzi, Marian Martí-Navas, Josep Puig, Antonio Moschetta, Alexandra Montagner, Pierre Gourdy, Christophe Heymes, Hervé Guillou, Valentina Tremaroli, José Manuel Fernández-Real, Sofia K Forslund, Remy Burcelin, Robert Caesar.
      Dietary lipids can affect metabolic health through gut microbiota-mediated mechanisms, but the influence of lipid-microbiota interaction on liver steatosis is largely unknown. We investigate the impact of dietary lipids on human gut microbiota composition and the effects of microbiota-lipid interactions on steatosis in male mice. In humans, low intake of saturated fatty acids (SFA) is associated with increased microbial diversity independent of fiber intake. In mice, poorly absorbed dietary long-chain SFA, particularly stearic acid, induce a shift in bile acid profile and improved metabolism and steatosis. These benefits are dependent on the gut microbiota, as they are transmitted by microbial transfer. Diets enriched in polyunsaturated fatty acids are protective against steatosis but have minor influence on the microbiota. In summary, we find that diets enriched in poorly absorbed long-chain SFA modulate gut microbiota profiles independent of fiber intake, and this interaction is relevant to improve metabolism and decrease liver steatosis.
    DOI:  https://doi.org/10.1038/s41467-023-41074-3
  30. Dev Cell. 2023 Aug 24. pii: S1534-5807(23)00397-0. [Epub ahead of print]
    Reconstructing human brown fat developmental trajectory in vitro.
    Jyoti Rao, Yannis Djeffal, Jerome Chal, Fabio Marchianò, Chih-Hao Wang, Ziad Al Tanoury, Svetlana Gapon, Alicia Mayeuf-Louchart, Ian Glass, Elizabeth M Sefton, Bianca Habermann, Gabrielle Kardon, Fiona M Watt, Yu-Hua Tseng, Olivier Pourquié.
      Brown adipocytes (BAs) represent a specialized cell type that is able to uncouple nutrient catabolism from ATP generation to dissipate energy as heat. In humans, the brown fat tissue is composed of discrete depots found throughout the neck and trunk region. BAs originate from a precursor common to skeletal muscle, but their developmental trajectory remains poorly understood. Here, we used single-cell RNA sequencing to characterize the development of interscapular brown fat in mice. Our analysis identified a transient stage of BA differentiation characterized by the expression of the transcription factor GATA6. We show that recapitulating the sequence of signaling cues identified in mice can lead to efficient differentiation of BAs in vitro from human pluripotent stem cells. These precursors can in turn be efficiently converted into functional BAs that can respond to signals mimicking adrenergic stimuli by increasing their metabolism, resulting in heat production.
    Keywords:  GATA6; brown adipocytes; brown adipose tissue; directed differentiation; human pluripotent stem cells; metabolism; obesity
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.001
  31. Cell. 2023 Aug 31. pii: S0092-8674(23)00857-7. [Epub ahead of print]186(18): 3758-3775
    Biomarkers of aging for the identification and evaluation of longevity interventions.
    Biomarkers of Aging Consortium
      With the rapid expansion of aging biology research, the identification and evaluation of longevity interventions in humans have become key goals of this field. Biomarkers of aging are critically important tools in achieving these objectives over realistic time frames. However, the current lack of standards and consensus on the properties of a reliable aging biomarker hinders their further development and validation for clinical applications. Here, we advance a framework for the terminology and characterization of biomarkers of aging, including classification and potential clinical use cases. We discuss validation steps and highlight ongoing challenges as potential areas in need of future research. This framework sets the stage for the development of valid biomarkers of aging and their ultimate utilization in clinical trials and practice.
    DOI:  https://doi.org/10.1016/j.cell.2023.08.003
  32. Nat Commun. 2023 Aug 28. 14(1): 5247
    Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases.
    Erik Nutma, Nurun Fancy, Maria Weinert, Stergios Tsartsalis, Manuel C Marzin, Robert C J Muirhead, Irene Falk, Marjolein Breur, Joy de Bruin, David Hollaus, Robin Pieterman, Jasper Anink, David Story, Siddharthan Chandran, Jiabin Tang, Maria C Trolese, Takashi Saito, Takaomi C Saido, Katharine H Wiltshire, Paula Beltran-Lobo, Alexandra Phillips, Jack Antel, Luke Healy, Marie-France Dorion, Dylan A Galloway, Rochelle Y Benoit, Quentin Amossé, Kelly Ceyzériat, Aurélien M Badina, Enikö Kövari, Caterina Bendotti, Eleonora Aronica, Carola I Radulescu, Jia Hui Wong, Anna M Barron, Amy M Smith, Samuel J Barnes, David W Hampton, Paul van der Valk, Steven Jacobson, Owain W Howell, David Baker, Markus Kipp, Hannes Kaddatz, Benjamin B Tournier, Philippe Millet, Paul M Matthews, Craig S Moore, Sandra Amor, David R Owen.
      Microglial activation plays central roles in neuroinflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18 kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.
    DOI:  https://doi.org/10.1038/s41467-023-40937-z
  33. Nat Genet. 2023 Aug 28.
    Extremely sparse models of linkage disequilibrium in ancestrally diverse association studies.
    Pouria Salehi Nowbandegani, Anthony Wilder Wohns, Jenna L Ballard, Eric S Lander, Alex Bloemendal, Benjamin M Neale, Luke J O'Connor.
      Linkage disequilibrium (LD) is the correlation among nearby genetic variants. In genetic association studies, LD is often modeled using large correlation matrices, but this approach is inefficient, especially in ancestrally diverse studies. In the present study, we introduce LD graphical models (LDGMs), which are an extremely sparse and efficient representation of LD. LDGMs are derived from genome-wide genealogies; statistical relationships among alleles in the LDGM correspond to genealogical relationships among haplotypes. We published LDGMs and ancestry-specific LDGM precision matrices for 18 million common variants (minor allele frequency >1%) in five ancestry groups, validated their accuracy and demonstrated order-of-magnitude improvements in runtime for commonly used LD matrix computations. We implemented an extremely fast multiancestry polygenic prediction method, BLUPx-ldgm, which performs better than a similar method based on the reference LD correlation matrix. LDGMs will enable sophisticated methods that scale to ancestrally diverse genetic association data across millions of variants and individuals.
    DOI:  https://doi.org/10.1038/s41588-023-01487-8
  34. Cell. 2023 Aug 22. pii: S0092-8674(23)00852-8. [Epub ahead of print]
    Structure of the thrombopoietin-MPL receptor complex is a blueprint for biasing hematopoiesis.
    Naotaka Tsutsumi, Zahra Masoumi, Sophie C James, Julie A Tucker, Hauke Winkelmann, William Grey, Lora K Picton, Lucie Moss, Steven C Wilson, Nathanael A Caveney, Kevin M Jude, Cornelius Gati, Jacob Piehler, Ian S Hitchcock, K Christopher Garcia.
      Thrombopoietin (THPO or TPO) is an essential cytokine for hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation. Here, we report the 3.4 Å resolution cryoelectron microscopy structure of the extracellular TPO-TPO receptor (TpoR or MPL) signaling complex, revealing the basis for homodimeric MPL activation and providing a structural rationalization for genetic loss-of-function thrombocytopenia mutations. The structure guided the engineering of TPO variants (TPOmod) with a spectrum of signaling activities, from neutral antagonists to partial- and super-agonists. Partial agonist TPOmod decoupled JAK/STAT from ERK/AKT/CREB activation, driving a bias for megakaryopoiesis and platelet production without causing significant HSC expansion in mice and showing superior maintenance of human HSCs in vitro. These data demonstrate the functional uncoupling of the two primary roles of TPO, highlighting the potential utility of TPOmod in hematology research and clinical HSC transplantation.
    Keywords:  JAK-STAT; TpoR; c-MPL; cryo-EM; hematopoiesis; ligand engineering; mTOR; signaling; structure; thrombopoietin
    DOI:  https://doi.org/10.1016/j.cell.2023.07.037
  35. EMBO J. 2023 Aug 30. e113118
    ER stress induces caspase-2-tBID-GSDME-dependent cell death in neurons lytically infected with herpes simplex virus type 2.
    Fanghui Ren, Ryo Narita, Ahmad S Rashidi, Stefanie Fruhwürth, Zongliang Gao, Rasmus O Bak, Martin K Thomsen, Georges Mgm Verjans, Line S Reinert, Søren R Paludan.
      Neurotropic viruses, including herpes simplex virus (HSV) types 1 and 2, have the capacity to infect neurons and can cause severe diseases. This is associated with neuronal cell death, which may contribute to morbidity or even mortality if the infection is not controlled. However, the mechanistic details of HSV-induced neuronal cell death remain enigmatic. Here, we report that lytic HSV-2 infection of human neuron-like SH-SY5Y cells and primary human and murine brain cells leads to cell death mediated by gasdermin E (GSDME). HSV-2-induced GSDME-mediated cell death occurs downstream of replication-induced endoplasmic reticulum stress driven by inositol-requiring kinase 1α (IRE1α), leading to activation of caspase-2, cleavage of the pro-apoptotic protein BH3-interacting domain death agonist (BID), and mitochondria-dependent activation of caspase-3. Finally, necrotic neurons released alarmins, which activated inflammatory responses in human iPSC-derived microglia. In conclusion, lytic HSV infection in neurons activates an ER stress-driven pathway to execute GSDME-mediated cell death and promote inflammation.
    Keywords:  Herpes simplex virus; IRE1α; neurons; organelle stress; pyroptosis
    DOI:  https://doi.org/10.15252/embj.2022113118
  36. Cell. 2023 Aug 21. pii: S0092-8674(23)00862-0. [Epub ahead of print]
    PINK1, Keap1, and Rtnl1 regulate selective clearance of endoplasmic reticulum during development.
    Ruoxi Wang, Tina M Fortier, Fei Chai, Guangyan Miao, James L Shen, Lucas J Restrepo, Jeromy J DiGiacomo, Panagiotis D Velentzas, Eric H Baehrecke.
      Selective clearance of organelles, including endoplasmic reticulum (ER) and mitochondria, by autophagy plays an important role in cell health. Here, we describe a developmentally programmed selective ER clearance by autophagy. We show that Parkinson's disease-associated PINK1, as well as Atl, Rtnl1, and Trp1 receptors, regulate ER clearance by autophagy. The E3 ubiquitin ligase Parkin functions downstream of PINK1 and is required for mitochondrial clearance while having the opposite function in ER clearance. By contrast, Keap1 and the E3 ubiquitin ligase Cullin3 function downstream of PINK1 to regulate ER clearance by influencing Rtnl1 and Atl. PINK1 regulates a change in Keap1 localization and Keap1-dependent ubiquitylation of the ER-phagy receptor Rtnl1 to facilitate ER clearance. Thus, PINK1 regulates the selective clearance of ER and mitochondria by influencing the balance of Keap1- and Parkin-dependent ubiquitylation of substrates that determine which organelle is removed by autophagy.
    Keywords:  Drosophila; ER-phagy; Keap1; PINK1; Parkin; Rtnl1
    DOI:  https://doi.org/10.1016/j.cell.2023.08.008
  37. Commun Biol. 2023 Aug 31. 6(1): 892
    Leading basic modes of spontaneous activity drive individual functional connectivity organization in the resting human brain.
    Xi Chen, Haoda Ren, Zhonghua Tang, Ke Zhou, Liqin Zhou, Zhentao Zuo, Xiaohua Cui, Xiaosong Chen, Zonghua Liu, Yong He, Xuhong Liao.
      Spontaneous activity of the human brain provides a window to explore intrinsic principles of functional organization. However, most studies have focused on interregional functional connectivity. The principles underlying rich repertoires of instantaneous activity remain largely unknown. We apply a recently proposed eigen-microstate analysis to three resting-state functional MRI datasets to identify basic modes that represent fundamental activity patterns that coexist over time. We identify five leading basic modes that dominate activity fluctuations. Each mode exhibits a distinct functional system-dependent coactivation pattern and corresponds to specific cognitive profiles. In particular, the spatial pattern of the first leading basis mode shows the separation of activity between the default-mode and primary and attention regions. Based on theoretical modelling, we further reconstruct individual functional connectivity as the weighted superposition of coactivation patterns corresponding to these leading basic modes. Moreover, these leading basic modes capture sleep deprivation-induced changes in brain activity and interregional connectivity, primarily involving the default-mode and task-positive regions. Our findings reveal a dominant set of basic modes of spontaneous activity that reflect multiplexed interregional coordination and drive conventional functional connectivity, furthering the understanding of the functional significance of spontaneous brain activity.
    DOI:  https://doi.org/10.1038/s42003-023-05262-7
  38. Nat Commun. 2023 Aug 28. 14(1): 4977
    Dynamically regulated two-site interaction of viral RNA to capture host translation initiation factor.
    Shunsuke Imai, Hiroshi Suzuki, Yoshinori Fujiyoshi, Ichio Shimada.
      Many RNA viruses employ internal ribosome entry sites (IRESs) in their genomic RNA to commandeer the host's translational machinery for replication. The IRES from encephalomyocarditis virus (EMCV) interacts with eukaryotic translation initiation factor 4 G (eIF4G), recruiting the ribosomal subunit for translation. Here, we analyze the three-dimensional structure of the complex composed of EMCV IRES, the HEAT1 domain fragment of eIF4G, and eIF4A, by cryo-electron microscopy. Two distinct eIF4G-interacting domains on the IRES are identified, and complex formation changes the angle therebetween. Further, we explore the dynamics of these domains by using solution NMR spectroscopy, revealing conformational equilibria in the microsecond to millisecond timescale. In the lowly-populated conformations, the base-pairing register of one domain is shifted with the structural transition of the three-way junction, as in the complex structure. Our study provides insights into the viral RNA's sophisticated strategy for optimal docking to hijack the host protein.
    DOI:  https://doi.org/10.1038/s41467-023-40582-6
  39. Nat Commun. 2023 Aug 26. 14(1): 5231
    Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA signaling.
    Nicholas C Vierra, Luisa Ribeiro-Silva, Michael Kirmiz, Deborah van der List, Pradeep Bhandari, Olivia A Mack, James Carroll, Elodie Le Monnier, Sue A Aicher, Ryuichi Shigemoto, James S Trimmer.
      Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM) are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration of intracellular signaling machinery near ER-PM junctions allows these domains to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular compartmentalization of protein kinase A (PKA) signaling also regulates essential cellular functions, however, no specific association between PKA and ER-PM junctional domains is known. Here, we show that in brain neurons type I PKA is directed to Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and ER-resident VAP proteins results in the concentration of type I PKA between stacked ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome enables reciprocal regulation between PKA and Ca2+ signaling machinery to support Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal ER-PM junctions support a receptor-independent form of PKA signaling driven by membrane depolarization and intracellular Ca2+, allowing conversion of information encoded in electrical signals into biochemical changes universally recognized throughout the cell.
    DOI:  https://doi.org/10.1038/s41467-023-40930-6
  40. Nat Commun. 2023 Aug 29. 14(1): 5254
    Interrogating the viral dark matter of the rumen ecosystem with a global virome database.
    Ming Yan, Akbar Adjie Pratama, Sripoorna Somasundaram, Zongjun Li, Yu Jiang, Matthew B Sullivan, Zhongtang Yu.
      The diverse rumen virome can modulate the rumen microbiome, but it remains largely unexplored. Here, we mine 975 published rumen metagenomes for viral sequences, create a global rumen virome database (RVD), and analyze the rumen virome for diversity, virus-host linkages, and potential roles in affecting rumen functions. Containing 397,180 species-level viral operational taxonomic units (vOTUs), RVD substantially increases the detection rate of rumen viruses from metagenomes compared with IMG/VR V3. Most of the classified vOTUs belong to Caudovirales, differing from those found in the human gut. The rumen virome is predicted to infect the core rumen microbiome, including fiber degraders and methanogens, carries diverse auxiliary metabolic genes, and thus likely impacts the rumen ecosystem in both a top-down and a bottom-up manner. RVD and the findings provide useful resources and a baseline framework for future research to investigate how viruses may impact the rumen ecosystem and digestive physiology.
    DOI:  https://doi.org/10.1038/s41467-023-41075-2
  41. Nat Methods. 2023 Aug 28.
    scNanoHi-C: a single-cell long-read concatemer sequencing method to reveal high-order chromatin structures within individual cells.
    Wen Li, Jiansen Lu, Ping Lu, Yun Gao, Yichen Bai, Kexuan Chen, Xinjie Su, Mengyao Li, Jun'e Liu, Yijun Chen, Lu Wen, Fuchou Tang.
      The high-order three-dimensional (3D) organization of regulatory genomic elements provides a topological basis for gene regulation, but it remains unclear how multiple regulatory elements across the mammalian genome interact within an individual cell. To address this, herein, we developed scNanoHi-C, which applies Nanopore long-read sequencing to explore genome-wide proximal high-order chromatin contacts within individual cells. We show that scNanoHi-C can reliably and effectively profile 3D chromatin structures and distinguish structure subtypes among individual cells. This method could also be used to detect genomic variations, including copy-number variations and structural variations, as well as to scaffold the de novo assembly of single-cell genomes. Notably, our results suggest that extensive high-order chromatin structures exist in active chromatin regions across the genome, and multiway interactions between enhancers and their target promoters were systematically identified within individual cells. Altogether, scNanoHi-C offers new opportunities to investigate high-order 3D genome structures at the single-cell level.
    DOI:  https://doi.org/10.1038/s41592-023-01978-w
  42. Cell. 2023 Aug 24. pii: S0092-8674(23)00855-3. [Epub ahead of print]
    Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation.
    Seung Cho Lee, Dexter W Adams, Jonathan J Ipsaro, Jonathan Cahn, Jason Lynn, Hyun-Soo Kim, Benjamin Berube, Viktoria Major, Joseph P Calarco, Chantal LeBlanc, Sonali Bhattacharjee, Umamaheswari Ramu, Daniel Grimanelli, Yannick Jacob, Philipp Voigt, Leemor Joshua-Tor, Robert A Martienssen.
      Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1LSH/HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance.
    Keywords:  DNA methylation; DNA replication; chromatin remodeling; epigenetic inheritance; heterochromatin; histone H3.1; histone H3.3; histone MGH3/HTR10; histone modification; transposable elements
    DOI:  https://doi.org/10.1016/j.cell.2023.08.001
  43. Nat Commun. 2023 Aug 26. 14(1): 5219
    Practical diagnosis of cirrhosis in non-alcoholic fatty liver disease using currently available non-invasive fibrosis tests.
    AFEF group for the study of liver fibrosis
      Unlike for advanced liver fibrosis, the practical rules for the early non-invasive diagnosis of cirrhosis in NAFLD remain not well defined. Here, we report the derivation and validation of a stepwise diagnostic algorithm in 1568 patients with NAFLD and liver biopsy coming from four independent cohorts. The study algorithm, using first the elastography-based tests Agile3+ and Agile4 and then the specialized blood tests FibroMeterV3G and CirrhoMeterV3G, provides stratification in four groups, the last of which is enriched in cirrhosis (71% prevalence in the validation set). A risk prediction chart is also derived to allow estimation of the individual probability of cirrhosis. The predicted risk shows excellent calibration in the validation set, and mean difference with perfect prediction is only -2.9%. These tools improve the personalized non-invasive diagnosis of cirrhosis in NAFLD.
    DOI:  https://doi.org/10.1038/s41467-023-40328-4
  44. Nature. 2023 Aug 31.
    Strike at outbreak-alert service ProMED to end - but tensions remain.
    Max Kozlov.
      
    Keywords:  Diseases; Public health; Scientific community
    DOI:  https://doi.org/10.1038/d41586-023-02750-y
  45. Nature. 2023 Aug 30.
    Neutralization, effector function and immune imprinting of Omicron variants.
    Amin Addetia, Luca Piccoli, James Brett Case, Young-Jun Park, Martina Beltramello, Barbara Guarino, Ha Dang, Guilherme Dias de Melo, Dora Pinto, Kaitlin Sprouse, Suzanne M Scheaffer, Jessica Bassi, Chiara Silacci-Fregni, Francesco Muoio, Marco Dini, Lucia Vincenzetti, Rima Acosta, Daisy Johnson, Sambhavi Subramanian, Christian Saliba, Martina Giurdanella, Gloria Lombardo, Giada Leoni, Katja Culap, Carley McAlister, Anushka Rajesh, Exequiel Dellota, Jiayi Zhou, Nisar Farhat, Dana Bohan, Julia Noack, Alex Chen, Florian A Lempp, Joel Quispe, Lauriane Kergoat, Florence Larrous, Elisabetta Cameroni, Bradley Whitener, Olivier Giannini, Pietro Cippà, Alessandro Ceschi, Paolo Ferrari, Alessandra Franzetti-Pellanda, Maira Biggiogero, Christian Garzoni, Stephanie Zappi, Luca Bernasconi, Min Jeong Kim, Laura E Rosen, Gretja Schnell, Nadine Czudnochowski, Fabio Benigni, Nicholas Franko, Jennifer K Logue, Courtney Yoshiyama, Cameron Stewart, Helen Chu, Hervé Bourhy, Michael A Schmid, Lisa A Purcell, Gyorgy Snell, Antonio Lanzavecchia, Michael S Diamond, Davide Corti, David Veesler.
      Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.
    DOI:  https://doi.org/10.1038/s41586-023-06487-6
  46. Nat Commun. 2023 Aug 30. 14(1): 5281
    Targeted mechanical stimulation via magnetic nanoparticles guides in vitro tissue development.
    Abdel Rahman Abdel Fattah, Niko Kolaitis, Katrien Van Daele, Brian Daza, Andika Gregorius Rustandi, Adrian Ranga.
      Tissues take shape through a series of morphogenetic movements guided by local cell-scale mechanical forces. Current in vitro approaches to recapitulate tissue mechanics rely on uncontrolled self-organization or on the imposition of extrinsic and homogenous forces using matrix or instrument-driven stimulation, thereby failing to recapitulate highly localized and spatially varying forces. Here we develop a method for targeted mechanical stimulation of organoids using embedded magnetic nanoparticles. We show that magnetic clusters within organoids can be produced by sequential aggregation of magnetically labeled and non-labeled human pluripotent stem cells. These clusters impose local mechanical forces on the surrounding cells in response to applied magnetic fields. We show that precise, spatially defined actuation provides short-term mechanical tissue perturbations as well as long-term cytoskeleton remodeling in these organoids, which we term "magnetoids". We demonstrate that targeted magnetic nanoparticle-driven actuation guides asymmetric tissue growth and proliferation, leading to enhanced patterning in human neural magnetoids. This approach, enabled by nanoparticle technology, allows for precise and locally controllable mechanical actuation in human neural tube organoids, and could be widely applicable to interrogate the role of local mechanotransduction in developmental and disease model systems.
    DOI:  https://doi.org/10.1038/s41467-023-41037-8
  47. Nat Cell Biol. 2023 Aug 28.
    A non-coding m6A reader promotes leukaemia.
    James Russell, Konstantinos Tzelepis.
      
    DOI:  https://doi.org/10.1038/s41556-023-01205-w
  48. Cell Host Microbe. 2023 Aug 21. pii: S1931-3128(23)00326-8. [Epub ahead of print]
    Pathogen-driven CRISPR screens identify TREX1 as a regulator of DNA self-sensing during influenza virus infection.
    Cason R King, Yiping Liu, Katherine A Amato, Grace A Schaack, Clayton Mickelson, Autumn E Sanders, Tony Hu, Srishti Gupta, Ryan A Langlois, Judith A Smith, Andrew Mehle.
      Host:pathogen interactions dictate the outcome of infection, yet the limitations of current approaches leave large regions of this interface unexplored. Here, we develop a novel fitness-based screen that queries factors important during the middle to late stages of infection. This is achieved by engineering influenza virus to direct the screen by programming dCas9 to modulate host gene expression. Our genome-wide screen for pro-viral factors identifies the cytoplasmic DNA exonuclease TREX1. TREX1 degrades cytoplasmic DNA to prevent inappropriate innate immune activation by self-DNA. We reveal that this same process aids influenza virus replication. Infection triggers release of mitochondrial DNA into the cytoplasm, activating antiviral signaling via cGAS and STING. TREX1 metabolizes the DNA, preventing its sensing. Collectively, these data show that self-DNA is deployed to amplify innate immunity, a process tempered by TREX1. Moreover, they demonstrate the power and generality of pathogen-driven fitness-based screens to pinpoint key host regulators of infection.
    Keywords:  CRISPR activation; TREX1; fitness-based screen; influenza virus; mtDNA
    DOI:  https://doi.org/10.1016/j.chom.2023.08.001
  49. Nat Chem Biol. 2023 Aug 31.
    Hydroxytryptophan biosynthesis by a family of heme-dependent enzymes in bacteria.
    Xinjie Shi, Guiyun Zhao, Hu Li, Zhijie Zhao, Wei Li, Miaolian Wu, Yi-Ling Du.
      Hydroxytryptophan serves as a chemical precursor to a variety of bioactive specialized metabolites, including the human neurotransmitter serotonin and the hormone melatonin. Although the human and animal routes to hydroxytryptophan have been known for decades, how bacteria catalyze tryptophan indole hydroxylation remains a mystery. Here we report a class of tryptophan hydroxylases that are involved in various bacterial metabolic pathways. These enzymes utilize a histidine-ligated heme cofactor and molecular oxygen or hydrogen peroxide to catalyze regioselective hydroxylation on the tryptophan indole moiety, which is mechanistically distinct from their animal counterparts from the nonheme iron enzyme family. Through genome mining, we also identify members that can hydroxylate the tryptophan indole ring at alternative positions. Our results not only reveal a conserved way to synthesize hydroxytryptophans in bacteria but also provide a valuable enzyme toolbox for biocatalysis. As proof of concept, we assemble a highly efficient pathway for melatonin in a bacterial host.
    DOI:  https://doi.org/10.1038/s41589-023-01416-0
  50. Nat Commun. 2023 Aug 29. 14(1): 4785
    Delayed gut microbiota maturation in the first year of life is a hallmark of pediatric allergic disease.
    Courtney Hoskinson, Darlene L Y Dai, Kate L Del Bel, Allan B Becker, Theo J Moraes, Piushkumar J Mandhane, B Brett Finlay, Elinor Simons, Anita L Kozyrskyj, Meghan B Azad, Padmaja Subbarao, Charisse Petersen, Stuart E Turvey.
      Allergic diseases affect millions of people worldwide. An increase in their prevalence has been associated with alterations in the gut microbiome, i.e., the microorganisms and their genes within the gastrointestinal tract. Maturation of the infant immune system and gut microbiota occur in parallel; thus, the conformation of the microbiome may determine if tolerant immune programming arises within the infant. Here we show, using deeply phenotyped participants in the CHILD birth cohort (n = 1115), that there are early-life influences and microbiome features which are uniformly associated with four distinct allergic diagnoses at 5 years: atopic dermatitis (AD, n = 367), asthma (As, n = 165), food allergy (FA, n = 136), and allergic rhinitis (AR, n = 187). In a subset with shotgun metagenomic and metabolomic profiling (n = 589), we discover that impaired 1-year microbiota maturation may be universal to pediatric allergies (AD p = 0.000014; As p = 0.0073; FA p = 0.00083; and AR p = 0.0021). Extending this, we find a core set of functional and metabolic imbalances characterized by compromised mucous integrity, elevated oxidative activity, decreased secondary fermentation, and elevated trace amines, to be a significant mediator between microbiota maturation at age 1 year and allergic diagnoses at age 5 years (βindirect = -2.28; p = 0.0020). Microbiota maturation thus provides a focal point to identify deviations from normative development to predict and prevent allergic disease.
    DOI:  https://doi.org/10.1038/s41467-023-40336-4
  51. Nat Rev Immunol. 2023 Aug 31.
    CODEX multiplexed tissue imaging.
    Yury Goltsev, Garry Nolan.
      
    DOI:  https://doi.org/10.1038/s41577-023-00936-z
  52. Science. 2023 Sep;381(6661): 944-946
    Unanswered questions about the causes of obesity.
    John R Speakman, Thorkild I A Sørensen, Kevin D Hall, David B Allison.
      Obesity is now a global pandemic, but there is little consensus about the causes.
    DOI:  https://doi.org/10.1126/science.adg2718
  53. Nat Commun. 2023 Aug 28. 14(1): 5242
    CircRREB1 mediates lipid metabolism related senescent phenotypes in chondrocytes through FASN post-translational modifications.
    Zhe Gong, Jinjin Zhu, Junxin Chen, Fan Feng, Haitao Zhang, Zheyuan Zhang, Chenxin Song, Kaiyu Liang, Shuhui Yang, Shunwu Fan, Xiangqian Fang, Shuying Shen.
      Osteoarthritis is a prevalent age-related disease characterized by dysregulation of extracellular matrix metabolism, lipid metabolism, and upregulation of senescence-associated secretory phenotypes. Herein, we clarify that CircRREB1 is highly expressed in secondary generation chondrocytes and its deficiency can alleviate FASN related senescent phenotypes and osteoarthritis progression. CircRREB1 impedes proteasome-mediated degradation of FASN by inhibiting acetylation-mediated ubiquitination. Meanwhile, CircRREB1 induces RanBP2-mediated SUMOylation of FASN and enhances its protein stability. CircRREB1-FASN axis inhibits FGF18 and FGFR3 mediated PI3K-AKT signal transduction, then increased p21 expression. Intra-articular injection of adenovirus-CircRreb1 reverses the protective effects in CircRreb1 deficiency mice. Further therapeutic interventions could have beneficial effects in identifying CircRREB1 as a potential prognostic and therapeutic target for age-related OA.
    DOI:  https://doi.org/10.1038/s41467-023-40975-7
  54. Nat Cell Biol. 2023 Aug 28.
    RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.
    Xiaoyang Dou, Yu Xiao, Chao Shen, Kitty Wang, Tong Wu, Chang Liu, Yini Li, Xianbin Yu, Jun Liu, Qing Dai, Kinga Pajdzik, Chang Ye, Ruiqi Ge, Boyang Gao, Jianhua Yu, Shuying Sun, Mengjie Chen, Jianjun Chen, Chuan He.
      N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.
    DOI:  https://doi.org/10.1038/s41556-023-01213-w
  55. J Exp Med. 2023 Nov 06. pii: e20222105. [Epub ahead of print]220(11):
    A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation.
    William T Ralvenius, Alison E Mungenast, Hannah Woolf, Margaret M Huston, Tyler Z Gillingham, Stephen K Godin, Jay Penney, Hugh P Cam, Fan Gao, Celia G Fernandez, Barbara Czako, Yaima Lightfoot, William J Ray, Adrian Beckmann, Alison M Goate, Edoardo Marcora, Carmen Romero-Molina, Pinar Ayata, Anne Schaefer, Elizabeta Gjoneska, Li-Huei Tsai.
      Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders.
    DOI:  https://doi.org/10.1084/jem.20222105
  56. Nature. 2023 Aug 31.
    Human ancestors nearly went extinct 900,000 years ago.
    Anna Ikarashi.
      
    Keywords:  Anthropology; Archaeology; Evolution
    DOI:  https://doi.org/10.1038/d41586-023-02712-4
  57. Nat Commun. 2023 Aug 30. 14(1): 5287
    Critical dynamics arise during structured information presentation within embodied in vitro neuronal networks.
    Forough Habibollahi, Brett J Kagan, Anthony N Burkitt, Chris French.
      Understanding how brains process information is an incredibly difficult task. Amongst the metrics characterising information processing in the brain, observations of dynamic near-critical states have generated significant interest. However, theoretical and experimental limitations associated with human and animal models have precluded a definite answer about when and why neural criticality arises with links from attention, to cognition, and even to consciousness. To explore this topic, we used an in vitro neural network of cortical neurons that was trained to play a simplified game of 'Pong' to demonstrate Synthetic Biological Intelligence (SBI). We demonstrate that critical dynamics emerge when neural networks receive task-related structured sensory input, reorganizing the system to a near-critical state. Additionally, better task performance correlated with proximity to critical dynamics. However, criticality alone is insufficient for a neuronal network to demonstrate learning in the absence of additional information regarding the consequences of previous actions. These findings offer compelling support that neural criticality arises as a base feature of incoming structured information processing without the need for higher order cognition.
    DOI:  https://doi.org/10.1038/s41467-023-41020-3
  58. Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302720120
    Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
    EADB
      Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
    Keywords:  Alzheimer’s dementia; HLA; Parkinson’s disease; autoimmunity; neurodegeneration
    DOI:  https://doi.org/10.1073/pnas.2302720120
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