bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒09‒18
38 papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.
  2. Induction of natural IgE by glucocorticoids.
  3. Independent phenotypic plasticity axes define distinct obesity sub-types.
  4. Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm.
  5. Mettl3-dependent m6A modification attenuates the brain stress response in Drosophila.
  6. Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro.
  7. Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.
  8. Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis.
  9. SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.
  10. OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
  11. Ketogenic diet uncovers differential metabolic plasticity of brain cells.
  12. Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.
  13. mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
  14. Triglyceride lipolysis triggers liquid crystalline phases in lipid droplets and alters the LD proteome.
  15. PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development.
  16. Treatment of Genetic Diseases With CRISPR Genome Editing.
  17. Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy.
  18. Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing.
  19. Tissue-restricted inhibition of mTOR using chemical genetics.
  20. Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.
  21. The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity.
  22. A temporal sequence of thalamic activity unfolds at transitions in behavioral arousal state.
  23. FBXW7 inactivation induces cellular senescence via accumulation of p53.
  24. Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
  25. Hepatocytes deficient in nuclear envelope protein lamina-associated polypeptide 1 are an ideal mammalian system to study intranuclear lipid droplets.
  26. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.
  27. Control of ribosomal RNA synthesis by hematopoietic transcription factors.
  28. How deadly is monkeypox? What scientists know.
  29. Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood.
  30. Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells.
  31. Biological ageing with HIV infection: evaluating the geroscience hypothesis.
  32. Detection of m6A RNA modifications at single-nucleotide resolution using m6A-selective allyl chemical labeling and sequencing.
  33. SnapShot: Mechanotransduction in the nucleus.
  34. Independent origins of fetal liver haematopoietic stem and progenitor cells.
  35. GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway.
  36. Liver macrophages in health and disease.
  37. Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
  38. Glucose-driven TOR-FIE-PRC2 signalling controls plant development.
  1. Nat Commun. 2022 Sep 12. 13(1): 5350
    Clonal hematopoiesis of indeterminate potential, DNA methylation, and risk for coronary artery disease.
    M D Mesbah Uddin, Ngoc Quynh H Nguyen, Bing Yu, Jennifer A Brody, Akhil Pampana, Tetsushi Nakao, Myriam Fornage, Jan Bressler, Nona Sotoodehnia, Joshua S Weinstock, Michael C Honigberg, Daniel Nachun, Romit Bhattacharya, Gabriel K Griffin, Varuna Chander, Richard A Gibbs, Jerome I Rotter, Chunyu Liu, Andrea A Baccarelli, Daniel I Chasman, Eric A Whitsel, Douglas P Kiel, Joanne M Murabito, Eric Boerwinkle, Benjamin L Ebert, Siddhartha Jaiswal, James S Floyd, Alexander G Bick, Christie M Ballantyne, Bruce M Psaty, Pradeep Natarajan, Karen N Conneely.
      Age-related changes to the genome-wide DNA methylation (DNAm) pattern observed in blood are well-documented. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by the age-related acquisition and expansion of leukemogenic mutations in hematopoietic stem cells (HSCs), is associated with blood cancer and coronary artery disease (CAD). Epigenetic regulators DNMT3A and TET2 are the two most frequently mutated CHIP genes. Here, we present results from an epigenome-wide association study for CHIP in 582 Cardiovascular Health Study (CHS) participants, with replication in 2655 Atherosclerosis Risk in Communities (ARIC) Study participants. We show that DNMT3A and TET2 CHIP have distinct and directionally opposing genome-wide DNAm association patterns consistent with their regulatory roles, albeit both promoting self-renewal of HSCs. Mendelian randomization analyses indicate that a subset of DNAm alterations associated with these two leading CHIP genes may promote the risk for CAD.
    DOI:  https://doi.org/10.1038/s41467-022-33093-3
  2. J Exp Med. 2022 Oct 03. pii: e20220903. [Epub ahead of print]219(10):
    Induction of natural IgE by glucocorticoids.
    Jaechul Lim, Erica V Lin, Jun Young Hong, Bharat Vaidyanathan, Steven A Erickson, Charles Annicelli, Ruslan Medzhitov.
      IgE mediates allergic responses by coating mast cell or basophil surfaces and inducing degranulation upon binding a specific allergen. IgE can also be spontaneously produced in the absence of foreign allergens; yet the origin, regulation, and functions of such "natural" IgE still remain largely unknown. Here, we find that glucocorticoids enhance the production of IgE in B cells both in vivo and ex vivo without antigenic challenge. Such IgE production is promoted by B cell-intrinsic glucocorticoid receptor signaling that reinforces CD40 signaling and synergizes with the IL-4/STAT6 pathway. In addition, we found that rare B cells in the mesenteric lymph nodes are responsible for the production of glucocorticoid-inducible IgE. Furthermore, locally produced glucocorticoids in the gut may induce natural IgE during perturbations of gut homeostasis, such as dysbiosis. Notably, mice preemptively treated with glucocorticoids were protected from subsequent pathogenic anaphylaxis. Together, our results suggest that glucocorticoids, classically considered to be broadly immunosuppressive, have a selective immunostimulatory role in B cells.
    DOI:  https://doi.org/10.1084/jem.20220903
  3. Nat Metab. 2022 Sep 12.
    Independent phenotypic plasticity axes define distinct obesity sub-types.
    PERMUTE
      Studies in genetically 'identical' individuals indicate that as much as 50% of complex trait variation cannot be traced to genetics or to the environment. The mechanisms that generate this 'unexplained' phenotypic variation (UPV) remain largely unknown. Here, we identify neuronatin (NNAT) as a conserved factor that buffers against UPV. We find that Nnat deficiency in isogenic mice triggers the emergence of a bi-stable polyphenism, where littermates emerge into adulthood either 'normal' or 'overgrown'. Mechanistically, this is mediated by an insulin-dependent overgrowth that arises from histone deacetylase (HDAC)-dependent β-cell hyperproliferation. A multi-dimensional analysis of monozygotic twin discordance reveals the existence of two patterns of human UPV, one of which (Type B) phenocopies the NNAT-buffered polyphenism identified in mice. Specifically, Type-B monozygotic co-twins exhibit coordinated increases in fat and lean mass across the body; decreased NNAT expression; increased HDAC-responsive gene signatures; and clinical outcomes linked to insulinemia. Critically, the Type-B UPV signature stratifies both childhood and adult cohorts into four metabolic states, including two phenotypically and molecularly distinct types of obesity.
    DOI:  https://doi.org/10.1038/s42255-022-00629-2
  4. Nat Commun. 2022 Sep 13. 13(1): 5347
    Interleukin-1 contributes to clonal expansion and progression of bone marrow fibrosis in JAK2V617F-induced myeloproliferative neoplasm.
    Mohammed Ferdous-Ur Rahman, Yue Yang, Bao T Le, Avik Dutta, Julia Posyniak, Patrick Faughnan, Mohammad A Sayem, Nadine S Aguilera, Golam Mohi.
      Chronic inflammation is frequently associated with myeloproliferative neoplasms (MPN), but the role of inflammation in the pathogenesis of MPN remains unclear. Expression of the proinflammatory cytokine interleukin-1 (IL-1) is elevated in patients with MPN as well as in Jak2V617F knock-in mice. Here, we show that genetic deletion of IL-1 receptor 1 (IL-1R1) normalizes peripheral blood counts, reduces splenomegaly and ameliorates bone marrow fibrosis in homozygous Jak2V617F mouse model of myelofibrosis. Deletion of IL-1R1 also significantly reduces Jak2V617F mutant hematopoietic stem/progenitor cells. Exogenous administration of IL-1β enhances myeloid cell expansion and accelerates the development of bone marrow fibrosis in heterozygous Jak2V617F mice. Furthermore, treatment with anti-IL-1R1 antibodies significantly reduces leukocytosis and splenomegaly, and ameliorates bone marrow fibrosis in homozygous Jak2V617F mice. Collectively, these results suggest that IL-1 signaling plays a pathogenic role in MPN disease progression, and targeting of IL-1R1 could be a useful strategy for the treatment of myelofibrosis.
    DOI:  https://doi.org/10.1038/s41467-022-32928-3
  5. Nat Commun. 2022 Sep 14. 13(1): 5387
    Mettl3-dependent m6A modification attenuates the brain stress response in Drosophila.
    Alexandra E Perlegos, Emily J Shields, Hui Shen, Kathy Fange Liu, Nancy M Bonini.
      N6-methyladenosine (m6A), the most prevalent internal modification on eukaryotic mRNA, plays an essential role in various stress responses. The brain is uniquely vulnerable to cellular stress, thus defining how m6A sculpts the brain's susceptibility may provide insight to brain aging and disease-related stress. Here we investigate the impact of m6A mRNA methylation in the adult Drosophila brain with stress. We show that m6A is enriched in the adult brain and increases with heat stress. Through m6A-immunoprecipitation sequencing, we show 5'UTR Mettl3-dependent m6A is enriched in transcripts of neuronal processes and signaling pathways that increase upon stress. Mettl3 knockdown results in increased levels of m6A targets and confers resilience to stress. We find loss of Mettl3 results in decreased levels of nuclear m6A reader Ythdc1, and knockdown of Ythdc1 also leads to stress resilience. Overall, our data suggest that m6A modification in Drosophila dampens the brain's biological response to stress.
    DOI:  https://doi.org/10.1038/s41467-022-33085-3
  6. Nat Commun. 2022 Sep 15. 13(1): 5427
    Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro.
    Tulsi Patel, Jennifer Hammelman, Siaresh Aziz, Sumin Jang, Michael Closser, Theodore L Michaels, Jacob A Blum, David K Gifford, Hynek Wichterle.
      Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age. While motifs of selector transcription factors, ISL1 and LHX3, are enriched in nascent regulatory regions, motifs of NFI factors, activity-dependent factors, and hormone receptors become more prominent in maturation-dependent enhancers. Notably, stem cell-derived motor neurons recapitulate ~40% of the maturation expression program in vitro, with neural activity playing only a modest role as a late-stage modulator. Thus, the genetic maturation program consists of a core hardwired subprogram that is correctly executed in vitro and an extrinsically-controlled subprogram that is dependent on the in vivo context of the maturing organism.
    DOI:  https://doi.org/10.1038/s41467-022-33022-4
  7. Nat Commun. 2022 Sep 15. 13(1): 5407
    Cryptococcal Hsf3 controls intramitochondrial ROS homeostasis by regulating the respiratory process.
    Xindi Gao, Yi Fu, Shengyi Sun, Tingyi Gu, Yanjian Li, Tianshu Sun, Hailong Li, Wei Du, Chenhao Suo, Chao Li, Yiru Gao, Yang Meng, Yue Ni, Sheng Yang, Tian Lan, Sixiang Sai, Jiayi Li, Kun Yu, Ping Wang, Chen Ding.
      Mitochondrial quality control prevents accumulation of intramitochondrial-derived reactive oxygen species (mtROS), thereby protecting cells against DNA damage, genome instability, and programmed cell death. However, underlying mechanisms are incompletely understood, particularly in fungal species. Here, we show that Cryptococcus neoformans heat shock factor 3 (CnHsf3) exhibits an atypical function in regulating mtROS independent of the unfolded protein response. CnHsf3 acts in nuclei and mitochondria, and nuclear- and mitochondrial-targeting signals are required for its organelle-specific functions. It represses the expression of genes involved in the tricarboxylic acid cycle while promoting expression of genes involved in electron transfer chain. In addition, CnHsf3 responds to multiple intramitochondrial stresses; this response is mediated by oxidation of the cysteine residue on its DNA binding domain, which enhances DNA binding. Our results reveal a function of HSF proteins in regulating mtROS homeostasis that is independent of the unfolded protein response.
    DOI:  https://doi.org/10.1038/s41467-022-33168-1
  8. Nat Commun. 2022 Sep 15. 13(1): 5408
    Liver group 2 innate lymphoid cells regulate blood glucose levels through IL-13 signaling and suppression of gluconeogenesis.
    Masanori Fujimoto, Masataka Yokoyama, Masahiro Kiuchi, Hiroyuki Hosokawa, Akitoshi Nakayama, Naoko Hashimoto, Ikki Sakuma, Hidekazu Nagano, Kazuyuki Yamagata, Fujimi Kudo, Ichiro Manabe, Eunyoung Lee, Ryo Hatano, Atsushi Onodera, Kiyoshi Hirahara, Koutaro Yokote, Takashi Miki, Toshinori Nakayama, Tomoaki Tanaka.
      The liver stores glycogen and releases glucose into the blood upon increased energy demand. Group 2 innate lymphoid cells (ILC2) in adipose and pancreatic tissues are known for their involvement in glucose homeostasis, but the metabolic contribution of liver ILC2s has not been studied in detail. Here we show that liver ILC2s are directly involved in the regulation of blood glucose levels. Mechanistically, interleukin (IL)-33 treatment induces IL-13 production in liver ILC2s, while directly suppressing gluconeogenesis in a specific Hnf4a/G6pc-high primary hepatocyte cluster via Stat3. These hepatocytes significantly interact with liver ILC2s via IL-13/IL-13 receptor signaling. The results of transcriptional complex analysis and GATA3-ChIP-seq, ATAC-seq, and scRNA-seq trajectory analyses establish a positive regulatory role for the transcription factor GATA3 in IL-13 production by liver ILC2s, while AP-1 family members are shown to suppress IL-13 release. Thus, we identify a regulatory role and molecular mechanism by which liver ILC2s contribute to glucose homeostasis.
    DOI:  https://doi.org/10.1038/s41467-022-33171-6
  9. Nat Commun. 2022 Sep 12. 13(1): 5341
    SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.
    Emilie Branche, Ying-Ting Wang, Karla M Viramontes, Joan M Valls Cuevas, Jialei Xie, Fernanda Ana-Sosa-Batiz, Norazizah Shafee, Sascha H Duttke, Rachel E McMillan, Alex E Clark, Michael N Nguyen, Aaron F Garretson, Jan J Crames, Nathan J Spann, Zhe Zhu, Jeremy N Rich, Deborah H Spector, Christopher Benner, Sujan Shresta, Aaron F Carlin.
      The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified. The results show that ZIKV infection specifically increases the expression of genes enriched for lipid metabolism-related functions. ZIKV infection also increases the recruitment of sterol regulatory element-binding protein (SREBP) transcription factors to lipid gene promoters, while pharmacologic inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of DCs. Our data thus identify SREBP2-activated transcription as a mechanism for promoting ZIKV infection amenable to therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41467-022-33041-1
  10. Cell Metab. 2022 Sep 08. pii: S1550-4131(22)00360-6. [Epub ahead of print]
    OMA1-mediated integrated stress response protects against ferroptosis in mitochondrial cardiomyopathy.
    Sofia Ahola, Pablo Rivera Mejías, Steffen Hermans, Srikanth Chandragiri, Patrick Giavalisco, Hendrik Nolte, Thomas Langer.
      Cardiomyopathy and heart failure are common manifestations in mitochondrial disease caused by deficiencies in the oxidative phosphorylation (OXPHOS) system of mitochondria. Here, we demonstrate that the cardiac-specific loss of the assembly factor Cox10 of the cytochrome c oxidase causes mitochondrial cardiomyopathy in mice, which is associated with OXPHOS deficiency, lysosomal defects, and an aberrant mitochondrial morphology. Activation of the mitochondrial peptidase Oma1 in Cox10-/- mice results in mitochondrial fragmentation and induction of the integrated stress response (ISR) along the Oma1-Dele1-Atf4 signaling axis. Ablation of Oma1 or Dele1 in Cox10-/- mice aggravates cardiomyopathy. ISR inhibition impairs the cardiac glutathione metabolism, limits the selenium-dependent accumulation of the glutathione peroxidase Gpx4, and increases lipid peroxidation in the heart, ultimately culminating in ferroptosis. Our results demonstrate a protective role of the Oma1-Dele1-mediated ISR in mitochondrial cardiomyopathy and link ferroptosis to OXPHOS deficiency and mitochondrial disease.
    Keywords:  Atf4; Dele1; Gpx4; Oma1; cardiomyopathy; ferroptosis; glutathione; integrated stress response; mitochondria; selenium
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.017
  11. Sci Adv. 2022 Sep 16. 8(37): eabo7639
    Ketogenic diet uncovers differential metabolic plasticity of brain cells.
    Tim Düking, Lena Spieth, Stefan A Berghoff, Lars Piepkorn, Annika M Schmidke, Miso Mitkovski, Nirmal Kannaiyan, Leon Hosang, Patricia Scholz, Ali H Shaib, Lennart V Schneider, Dörte Hesse, Torben Ruhwedel, Ting Sun, Lisa Linhoff, Andrea Trevisiol, Susanne Köhler, Adrian Marti Pastor, Thomas Misgeld, Michael Sereda, Imam Hassouna, Moritz J Rossner, Francesca Odoardi, Till Ischebeck, Livia de Hoz, Johannes Hirrlinger, Olaf Jahn, Gesine Saher.
      To maintain homeostasis, the body, including the brain, reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major central nervous system (CNS) cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Unexpectedly, the comparison with KD revealed distinct cell type-specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Moreover, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic cross-talk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.
    DOI:  https://doi.org/10.1126/sciadv.abo7639
  12. Nat Commun. 2022 Sep 15. 13(1): 5415
    Sirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling.
    Sneha Mishra, Claudia Cosentino, Ankit Kumar Tamta, Danish Khan, Shalini Srinivasan, Venkatraman Ravi, Elena Abbotto, Bangalore Prabhashankar Arathi, Shweta Kumar, Aditi Jain, Anand S Ramaian, Shruti M Kizkekra, Raksha Rajagopal, Swathi Rao, Swati Krishna, Ninitha Asirvatham-Jeyaraj, Elizabeth R Haggerty, Dafne M Silberman, Irwin J Kurland, Ravindra P Veeranna, Tamilselvan Jayavelu, Santina Bruzzone, Raul Mostoslavsky, Nagalingam R Sundaresan.
      Chronic activation of stress hormones such as glucocorticoids leads to skeletal muscle wasting in mammals. However, the molecular events that mediate glucocorticoid-induced muscle wasting are not well understood. Here, we show that SIRT6, a chromatin-associated deacetylase indirectly regulates glucocorticoid-induced muscle wasting by modulating IGF/PI3K/AKT signaling. Our results show that SIRT6 levels are increased during glucocorticoid-induced reduction of myotube size and during skeletal muscle atrophy in mice. Notably, overexpression of SIRT6 spontaneously decreases the size of primary myotubes in a cell-autonomous manner. On the other hand, SIRT6 depletion increases the diameter of myotubes and protects them against glucocorticoid-induced reduction in myotube size, which is associated with enhanced protein synthesis and repression of atrogenes. In line with this, we find that muscle-specific SIRT6 deficient mice are resistant to glucocorticoid-induced muscle wasting. Mechanistically, we find that SIRT6 deficiency hyperactivates IGF/PI3K/AKT signaling through c-Jun transcription factor-mediated increase in IGF2 expression. The increased activation, in turn, leads to nuclear exclusion and transcriptional repression of the FoxO transcription factor, a key activator of muscle atrophy. Further, we find that pharmacological inhibition of SIRT6 protects against glucocorticoid-induced muscle wasting in mice by regulating IGF/PI3K/AKT signaling implicating the role of SIRT6 in glucocorticoid-induced muscle atrophy.
    DOI:  https://doi.org/10.1038/s41467-022-32905-w
  13. Cell. 2022 Sep 08. pii: S0092-8674(22)01112-6. [Epub ahead of print]
    mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
    Antonio J Pagán, Lauren J Lee, Joy Edwards-Hicks, Cecilia B Moens, David M Tobin, Elisabeth M Busch-Nentwich, Erika L Pearce, Lalita Ramakrishnan.
      Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
    Keywords:  ESAT-6 mitotoxicity; Mycobacterium marinum; Mycobacterium tuberculosis; granuloma necrosis; mTOR; macrophage death; mitochondrial metabolism; oxidative phosphorylation; tuberculosis; zebrafish TB model
    DOI:  https://doi.org/10.1016/j.cell.2022.08.018
  14. J Cell Biol. 2022 Nov 07. pii: e202205053. [Epub ahead of print]221(11):
    Triglyceride lipolysis triggers liquid crystalline phases in lipid droplets and alters the LD proteome.
    Sean Rogers, Long Gui, Anastasiia Kovalenko, Valeria Zoni, Maxime Carpentier, Kamran Ramji, Kalthoum Ben Mbarek, Amelie Bacle, Patrick Fuchs, Pablo Campomanes, Evan Reetz, Natalie Ortiz Speer, Emma Reynolds, Abdou Rachid Thiam, Stefano Vanni, Daniela Nicastro, W Mike Henne.
      Lipid droplets (LDs) are reservoirs for triglycerides (TGs) and sterol-esters (SEs), but how these lipids are organized within LDs and influence their proteome remain unclear. Using in situ cryo-electron tomography, we show that glucose restriction triggers lipid phase transitions within LDs generating liquid crystalline lattices inside them. Mechanistically this requires TG lipolysis, which decreases the LD's TG:SE ratio, promoting SE transition to a liquid crystalline phase. Molecular dynamics simulations reveal TG depletion promotes spontaneous TG and SE demixing in LDs, additionally altering the lipid packing of the PL monolayer surface. Fluorescence imaging and proteomics further reveal that liquid crystalline phases are associated with selective remodeling of the LD proteome. Some canonical LD proteins, including Erg6, relocalize to the ER network, whereas others remain LD-associated. Model peptide LiveDrop also redistributes from LDs to the ER, suggesting liquid crystalline phases influence ER-LD interorganelle transport. Our data suggests glucose restriction drives TG mobilization, which alters the phase properties of LD lipids and selectively remodels the LD proteome.
    DOI:  https://doi.org/10.1083/jcb.202205053
  15. Commun Biol. 2022 Sep 14. 5(1): 961
    PU.1-c-Jun interaction is crucial for PU.1 function in myeloid development.
    Xinhui Zhao, Boris Bartholdy, Yukiya Yamamoto, Erica K Evans, Meritxell Alberich-Jordà, Philipp B Staber, Touati Benoukraf, Pu Zhang, Junyan Zhang, Bon Q Trinh, John D Crispino, Trang Hoang, Mahmoud A Bassal, Daniel G Tenen.
      The Ets transcription factor PU.1 is essential for inducing the differentiation of monocytes, macrophages, and B cells in fetal liver and adult bone marrow. PU.1 controls hematopoietic differentiation through physical interactions with other transcription factors, such as C/EBPα and the AP-1 family member c-Jun. We found that PU.1 recruits c-Jun to promoters without the AP-1 binding sites. To address the functional importance of this interaction, we generated PU.1 point mutants that do not bind c-Jun while maintaining normal DNA binding affinity. These mutants lost the ability to transactivate a target reporter that requires a physical PU.1-c-Jun interaction, and did not induce monocyte/macrophage differentiation of PU.1-deficient cells. Knock-in mice carrying these point mutations displayed an almost complete block in hematopoiesis and perinatal lethality. While the PU.1 mutants were expressed in hematopoietic stem and early progenitor cells, myeloid differentiation was severely blocked, leading to an almost complete loss of mature hematopoietic cells. Differentiation into mature macrophages could be restored by expressing PU.1 mutant fused to c-Jun, demonstrating that a physical PU.1-c-Jun interaction is crucial for the transactivation of PU.1 target genes required for myeloid commitment and normal PU.1 function in vivo during macrophage differentiation.
    DOI:  https://doi.org/10.1038/s42003-022-03888-7
  16. JAMA. 2022 09 13. 328(10): 980-981
    Treatment of Genetic Diseases With CRISPR Genome Editing.
    Matthew J Kan, Jennifer A Doudna.
      
    DOI:  https://doi.org/10.1001/jama.2022.13468
  17. Nat Med. 2022 Sep 12.
    Post-infusion CAR TReg cells identify patients resistant to CD19-CAR therapy.
    Zinaida Good, Jay Y Spiegel, Bita Sahaf, Meena B Malipatlolla, Zach J Ehlinger, Sreevidya Kurra, Moksha H Desai, Warren D Reynolds, Anita Wong Lin, Panayiotis Vandris, Fang Wu, Snehit Prabhu, Mark P Hamilton, John S Tamaresis, Paul J Hanson, Shabnum Patel, Steven A Feldman, Matthew J Frank, John H Baird, Lori Muffly, Gursharan K Claire, Juliana Craig, Katherine A Kong, Dhananjay Wagh, John Coller, Sean C Bendall, Robert J Tibshirani, Sylvia K Plevritis, David B Miklos, Crystal L Mackall.
      Approximately 60% of patients with large B cell lymphoma treated with chimeric antigen receptor (CAR) T cell therapies targeting CD19 experience disease progression, and neurotoxicity remains a challenge. Biomarkers associated with resistance and toxicity are limited. In this study, single-cell proteomic profiling of circulating CAR T cells in 32 patients treated with CD19-CAR identified that CD4+Helios+ CAR T cells on day 7 after infusion are associated with progressive disease and less severe neurotoxicity. Deep profiling demonstrated that this population is non-clonal and manifests hallmark features of T regulatory (TReg) cells. Validation cohort analysis upheld the link between higher CAR TReg cells with clinical progression and less severe neurotoxicity. A model combining expansion of this subset with lactate dehydrogenase levels, as a surrogate for tumor burden, was superior for predicting durable clinical response compared to models relying on each feature alone. These data credential CAR TReg cell expansion as a novel biomarker of response and toxicity after CAR T cell therapy and raise the prospect that this subset may regulate CAR T cell responses in humans.
    DOI:  https://doi.org/10.1038/s41591-022-01960-7
  18. Nat Biotechnol. 2022 Sep 15.
    Mostly natural sequencing-by-synthesis for scRNA-seq using Ultima sequencing.
    Sean K Simmons, Gila Lithwick-Yanai, Xian Adiconis, Florian Oberstrass, Nika Iremadze, Kathryn Geiger-Schuller, Pratiksha I Thakore, Chris J Frangieh, Omer Barad, Gilad Almogy, Orit Rozenblatt-Rosen, Aviv Regev, Doron Lipson, Joshua Z Levin.
      Here we introduce a mostly natural sequencing-by-synthesis (mnSBS) method for single-cell RNA sequencing (scRNA-seq), adapted to the Ultima genomics platform, and systematically benchmark it against current scRNA-seq technology. mnSBS uses mostly natural, unmodified nucleotides and only a low fraction of fluorescently labeled nucleotides, which allows for high polymerase processivity and lower costs. We demonstrate successful application in four scRNA-seq case studies of different technical and biological types, including 5' and 3' scRNA-seq, human peripheral blood mononuclear cells from a single individual and in multiplex, as well as Perturb-Seq. Benchmarking shows that results from mnSBS-based scRNA-seq are very similar to those using Illumina sequencing, with minor differences in results related to the position of reads relative to annotated gene boundaries, owing to single-end reads of Ultima being closer to gene ends than reads from Illumina. The method is thus compatible with state-of-the-art scRNA-seq libraries independent of the sequencing technology. We expect mnSBS to be of particular utility for cost-effective large-scale scRNA-seq projects.
    DOI:  https://doi.org/10.1038/s41587-022-01452-6
  19. Proc Natl Acad Sci U S A. 2022 Sep 20. 119(38): e2204083119
    Tissue-restricted inhibition of mTOR using chemical genetics.
    Douglas R Wassarman, Kondalarao Bankapalli, Leo J Pallanck, Kevan M Shokat.
      Mammalian target of rapamycin (mTOR) is a highly conserved eukaryotic protein kinase that coordinates cell growth and metabolism, and plays a critical role in cancer, immunity, and aging. It remains unclear how mTOR signaling in individual tissues contributes to whole-organism processes because mTOR inhibitors, like the natural product rapamycin, are administered systemically and target multiple tissues simultaneously. We developed a chemical-genetic system, termed selecTOR, that restricts the activity of a rapamycin analog to specific cell populations through targeted expression of a mutant FKBP12 protein. This analog has reduced affinity for its obligate binding partner FKBP12, which reduces its ability to inhibit mTOR in wild-type cells and tissues. Expression of the mutant FKBP12, which contains an expanded binding pocket, rescues the activity of this rapamycin analog. Using this system, we show that selective mTOR inhibition can be achieved in Saccharomyces cerevisiae and human cells, and we validate the utility of our system in an intact metazoan model organism by identifying the tissues responsible for a rapamycin-induced developmental delay in Drosophila.
    Keywords:  Drosophila; kinase inhibitor; mTOR; rapamycin; tissue specific
    DOI:  https://doi.org/10.1073/pnas.2204083119
  20. Nat Commun. 2022 Sep 10. 13(1): 5324
    Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis.
    Marie Bobowski-Gerard, Clémence Boulet, Francesco P Zummo, Julie Dubois-Chevalier, Céline Gheeraert, Mohamed Bou Saleh, Jean-Marc Strub, Amaury Farce, Maheul Ploton, Loïc Guille, Jimmy Vandel, Antonino Bongiovanni, Ninon Very, Eloïse Woitrain, Audrey Deprince, Fanny Lalloyer, Eric Bauge, Lise Ferri, Line-Carolle Ntandja-Wandji, Alexia K Cotte, Corinne Grangette, Emmanuelle Vallez, Sarah Cianférani, Violeta Raverdy, Robert Caiazzo, Viviane Gnemmi, Emmanuelle Leteurtre, Benoit Pourcet, Réjane Paumelle, Kim Ravnskjaer, Guillaume Lassailly, Joel T Haas, Philippe Mathurin, François Pattou, Laurent Dubuquoy, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute.
      Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.
    DOI:  https://doi.org/10.1038/s41467-022-33063-9
  21. J Clin Invest. 2022 Sep 15. pii: e147566. [Epub ahead of print]132(18):
    The FoxO4/DKK3 axis represses IFN-γ expression by Th1 cells and limits antimicrobial immunity.
    Xiang Chen, Jia Hu, Yunfei Wang, Younghee Lee, Xiaohong Zhao, Huiping Lu, Gengzhen Zhu, Hui Wang, Yu Jiang, Fan Liu, Yongzhen Chen, Byung-Seok Kim, Qinghua Zhou, Xindong Liu, Xiaohu Wang, Seon Hee Chang, Chen Dong.
      Forkhead box O transcriptional factors, especially FoxO1 and FoxO3a, play critical roles in physiologic and pathologic immune responses. However, the function of FoxO4, another main member of the FoxO family, in lymphoid cells is still poorly understood. Here, we showed that loss of FoxO4 in T cells augmented IFN-γ production of Th1 cells in vitro. Correspondingly, conditional deletion of FoxO4 in CD4+ T cells enhanced T cell-specific responses to Listeria monocytogenes infection in vivo. Genome-wide occupancy and transcriptomic analyses identified Dkk3 (encoding the Dickkopf-3 protein) as a direct transcriptional target of FoxO4. Consistent with the FoxO4-DKK3 relationship, recombinant DKK3 protein restored normal levels of IFN-γ production in FoxO4-deficient Th1 cells through the downregulation of lymphoid enhancer-binding factor 1 (Lef1) expression. Together, our data suggest a potential FoxO4/DKK3 axis in Th1 cell differentiation, providing what we believe to be an important insight and supplement for FoxO family proteins in T lymphocyte biology and revealing a promising target for the treatment of immune-related diseases.
    Keywords:  Bacterial infections; Cytokines; Immunology; Th1 response
    DOI:  https://doi.org/10.1172/JCI147566
  22. Nat Commun. 2022 Sep 16. 13(1): 5442
    A temporal sequence of thalamic activity unfolds at transitions in behavioral arousal state.
    Beverly Setzer, Nina E Fultz, Daniel E P Gomez, Stephanie D Williams, Giorgio Bonmassar, Jonathan R Polimeni, Laura D Lewis.
      Awakening from sleep reflects a profound transformation in neural activity and behavior. The thalamus is a key controller of arousal state, but whether its diverse nuclei exhibit coordinated or distinct activity at transitions in behavioral arousal state is unknown. Using fast fMRI at ultra-high field (7 Tesla), we measured sub-second activity across thalamocortical networks and within nine thalamic nuclei to delineate these dynamics during spontaneous transitions in behavioral arousal state. We discovered a stereotyped sequence of activity across thalamic nuclei and cingulate cortex that preceded behavioral arousal after a period of inactivity, followed by widespread deactivation. These thalamic dynamics were linked to whether participants subsequently fell back into unresponsiveness, with unified thalamic activation reflecting maintenance of behavior. These results provide an outline of the complex interactions across thalamocortical circuits that orchestrate behavioral arousal state transitions, and additionally, demonstrate that fast fMRI can resolve sub-second subcortical dynamics in the human brain.
    DOI:  https://doi.org/10.1038/s41467-022-33010-8
  23. Cell Death Dis. 2022 Sep 14. 13(9): 788
    FBXW7 inactivation induces cellular senescence via accumulation of p53.
    Longyuan Gong, Danrui Cui, Dian Liu, Xiao Shen, Hui Pan, Xiufang Xiong, Yongchao Zhao.
      F-box and WD repeat domain containing 7 (FBXW7) acts as a substrate receptor of SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase and plays crucial roles in the regulation of several cellular processes, including cell growth, division, and differentiation, by targeting diverse key regulators for degradation. However, its role in regulating cellular senescence remains elusive. Here, we found that FBXW7 inactivation by siRNA-based knockdown or CRISPR/Cas9-based knockout induced significant cellular senescence in p53 wild-type cells, but not in p53 mutant or null cells, along with activation of both the p53/p21 and p16INK4a/Rb pathways. Simultaneous p53 inactivation abrogated senescence and cell growth arrest induced by FBXW7 deficiency as well as the alteration of both the p53/p21 and p16INK4a/Rb pathways. Moreover, Fbxw7 deletion accelerated replicative senescence of primary mouse embryonic fibroblasts in a p53-dependent manner. In addition, FBXW7 deletion induced the senescence-associated secretory phenotype to trigger secondary senescence. Importantly, in a radiation-induced senescence mouse model, simultaneous deletion of p53 rescued accelerated senescence and aging caused by Fbxw7 loss. Thus, our study uncovered a novel role for FBXW7 in the regulation of senescence by eliminating p53.
    DOI:  https://doi.org/10.1038/s41419-022-05229-2
  24. J Cell Biol. 2022 Nov 07. pii: e202201160. [Epub ahead of print]221(11):
    Mitochondrial dysfunction triggers actin polymerization necessary for rapid glycolytic activation.
    Rajarshi Chakrabarti, Tak Shun Fung, Taewook Kang, Pieti W Elonkirjo, Anu Suomalainen, Edward J Usherwood, Henry N Higgs.
      Mitochondrial damage represents a dramatic change in cellular homeostasis. One rapid response is perimitochondrial actin polymerization, termed acute damage-induced actin (ADA). The consequences of ADA are not understood. In this study, we show evidence suggesting that ADA is linked to rapid glycolytic activation upon mitochondrial damage in multiple cells, including mouse embryonic fibroblasts and effector CD8+ T lymphocytes. ADA-inducing treatments include CCCP, antimycin, rotenone, oligomycin, and hypoxia. The Arp2/3 complex inhibitor CK666 or the mitochondrial sodium-calcium exchanger (NCLX) inhibitor CGP37157 inhibits both ADA and the glycolytic increase within 5 min, supporting ADA's role in glycolytic stimulation. Two situations causing chronic reductions in mitochondrial ATP production, mitochondrial DNA depletion and mutation to the NDUFS4 subunit of complex 1 of the electron transport chain, cause persistent perimitochondrial actin filaments similar to ADA. CK666 treatment causes rapid mitochondrial actin loss and a drop in ATP in NDUFS4 knock-out cells. We propose that ADA is necessary for rapid glycolytic activation upon mitochondrial impairment, to re-establish ATP production.
    DOI:  https://doi.org/10.1083/jcb.202201160
  25. J Lipid Res. 2022 Sep 10. pii: S0022-2275(22)00110-9. [Epub ahead of print] 100277
    Hepatocytes deficient in nuclear envelope protein lamina-associated polypeptide 1 are an ideal mammalian system to study intranuclear lipid droplets.
    Cecilia Östlund, Antonio Hernandez-Ono, Samantha J Turk, William T Dauer, Henry N Ginsberg, Howard J Worman, Ji-Yeon Shin.
      Lipid droplets (LDs) are generally considered to be synthesized in the ER and utilized in the cytoplasm. However, LDs have been observed inside nuclei in some cells, although recent research on nuclear LDs has focused on cultured cell lines. To better understand nuclear LDs that occur in vivo, here we examined LDs in primary hepatocytes from mice following depletion of the nuclear envelope protein lamina-associated polypeptide 1 (LAP1). Microscopic image analysis showed that LAP1-depleted hepatocytes contain frequent nuclear LDs, which differ from cytoplasmic LDs in their associated proteins. We found type 1 nucleoplasmic reticula, which are invaginations of the inner nuclear membrane, are often associated with nuclear LDs in these hepatocytes. Furthermore, in vivo depletion of the nuclear envelope proteins lamin A and C from mouse hepatocytes led to severely abnormal nuclear morphology, but significantly fewer nuclear LDs than were observed upon depletion of LAP1. In addition, we show both high fat diet feeding and fasting of mice increased cytoplasmic lipids in LAP1-depleted hepatocytes, but reduced nuclear LDs, demonstrating a relationship of LD formation with nutritional state. Finally, depletion of microsomal triglyceride transfer protein did not change the frequency of nuclear LDs in LAP1-depleted hepatocytes, suggesting that it is not required for the biogenesis of nuclear LDs in these cells. Together, these data show that LAP1-depleted hepatocytes represent an ideal mammalian system to investigate the biogenesis of nuclear LDs and their partitioning between the nucleus and cytoplasm in response to changes in nutritional state and cellular metabolism in vivo.
    Keywords:  animal models; cell biology; high-fat diet; lamin; lipid droplet; liver; mouse genetics; nucleus; nutritional state; type 1 nucleoplasmic reticula
    DOI:  https://doi.org/10.1016/j.jlr.2022.100277
  26. Nat Cell Biol. 2022 Sep 15.
    Single-cell atlas of human liver development reveals pathways directing hepatic cell fates.
    Brandon T Wesley, Alexander D B Ross, Daniele Muraro, Zhichao Miao, Sarah Saxton, Rute A Tomaz, Carola M Morell, Katherine Ridley, Ekaterini D Zacharis, Sandra Petrus-Reurer, Judith Kraiczy, Krishnaa T Mahbubani, Stephanie Brown, Jose Garcia-Bernardo, Clara Alsinet, Daniel Gaffney, Dave Horsfall, Olivia C Tysoe, Rachel A Botting, Emily Stephenson, Dorin-Mirel Popescu, Sonya MacParland, Gary Bader, Ian D McGilvray, Daniel Ortmann, Fotios Sampaziotis, Kourosh Saeb-Parsy, Muzlifah Haniffa, Kelly R Stevens, Matthias Zilbauer, Sarah A Teichmann, Ludovic Vallier.
      The liver has been studied extensively due to the broad number of diseases affecting its vital functions. However, therapeutic advances have been hampered by the lack of knowledge concerning human hepatic development. Here, we addressed this limitation by describing the developmental trajectories of different cell types that make up the human liver at single-cell resolution. These transcriptomic analyses revealed that sequential cell-to-cell interactions direct functional maturation of hepatocytes, with non-parenchymal cells playing essential roles during organogenesis. We utilized this information to derive bipotential hepatoblast organoids and then exploited this model system to validate the importance of signalling pathways in hepatocyte and cholangiocyte specification. Further insights into hepatic maturation also enabled the identification of stage-specific transcription factors to improve the functionality of hepatocyte-like cells generated from human pluripotent stem cells. Thus, our study establishes a platform to investigate the basic mechanisms directing human liver development and to produce cell types for clinical applications.
    DOI:  https://doi.org/10.1038/s41556-022-00989-7
  27. Mol Cell. 2022 Sep 09. pii: S1097-2765(22)00847-4. [Epub ahead of print]
    Control of ribosomal RNA synthesis by hematopoietic transcription factors.
    Charles Antony, Subin S George, Justin Blum, Patrick Somers, Chelsea L Thorsheim, Dexter J Wu-Corts, Yuxi Ai, Long Gao, Kaosheng Lv, Michel G Tremblay, Tom Moss, Kai Tan, Jeremy E Wilusz, Austen R D Ganley, Maxim Pimkin, Vikram R Paralkar.
      Ribosomal RNAs (rRNAs) are the most abundant cellular RNAs, and their synthesis from rDNA repeats by RNA polymerase I accounts for the bulk of all transcription. Despite substantial variation in rRNA transcription rates across cell types, little is known about cell-type-specific factors that bind rDNA and regulate rRNA transcription to meet tissue-specific needs. Using hematopoiesis as a model system, we mapped about 2,200 ChIP-seq datasets for 250 transcription factors (TFs) and chromatin proteins to human and mouse rDNA and identified robust binding of multiple TF families to canonical TF motifs on rDNA. Using a 47S-FISH-Flow assay developed for nascent rRNA quantification, we demonstrated that targeted degradation of C/EBP alpha (CEBPA), a critical hematopoietic TF with conserved rDNA binding, caused rapid reduction in rRNA transcription due to reduced RNA Pol I occupancy. Our work identifies numerous potential rRNA regulators and provides a template for dissection of TF roles in rRNA transcription.
    Keywords:  CEBPa; FISH; Polr1; RNA Pol I; RNA polymerase I; dTAG; degron; hematopoiesis; rDNA; rRNA; ribosome biogenesis; transcription factor
    DOI:  https://doi.org/10.1016/j.molcel.2022.08.027
  28. Nature. 2022 Sep;609(7928): 663
    How deadly is monkeypox? What scientists know.
    Max Kozlov.
      
    Keywords:  Diseases; Public health; Virology
    DOI:  https://doi.org/10.1038/d41586-022-02931-1
  29. JCI Insight. 2022 Sep 15. pii: e160854. [Epub ahead of print]
    Beta-cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood.
    Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout.
      Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children insulin resistance persists leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here we show that puberty is associated with a transient increase in β-cell proliferation in rats and humans of both sexes. In rats, β-cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β-cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-HT) pathway underwent changes consistent with proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β-cell proliferation in pubertal islets ex vivo and in vivo. Peri-pubertal metabolic stress blunted β-cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GHR/5-HT/HTR2B signaling in the control of β-cell mass expansion during puberty and a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.
    Keywords:  Beta cells; Endocrinology; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.160854
  30. Nat Commun. 2022 Sep 14. 13(1): 5399
    Mild dyslipidemia accelerates tumorigenesis through expansion of Ly6Chi monocytes and differentiation to pro-angiogenic myeloid cells.
    Thi Tran, Jean-Remi Lavillegrand, Cedric Lereverend, Bruno Esposito, Lucille Cartier, Melanie Montabord, Jaouen Tran-Rajau, Marc Diedisheim, Nadège Gruel, Khadija Ouguerram, Lea Paolini, Olivia Lenoir, Emmanuel Pinteaux, Eva Brabencova, Corinne Tanchot, Pauline Urquia, Jacqueline Lehmann-Che, Richard Le Naour, Yacine Merrouche, Christian Stockmann, Ziad Mallat, Alain Tedgui, Hafid Ait-Oufella, Eric Tartour, Stephane Potteaux.
      Cancer and cardiovascular disease (CVD) share common risk factors such as dyslipidemia, obesity and inflammation. However, the role of pro-atherogenic environment and its associated low-grade inflammation in tumor progression remains underexplored. Here we show that feeding C57BL/6J mice with a non-obesogenic high fat high cholesterol diet (HFHCD) for two weeks to induce mild dyslipidemia, increases the pool of circulating Ly6Chi monocytes available for initial melanoma development, in an IL-1β-dependent manner. Descendants of circulating myeloid cells, which accumulate in the tumor microenvironment of mice under HFHCD, heighten pro-angiogenic and immunosuppressive activities locally. Limiting myeloid cell accumulation or targeting VEGF-A production by myeloid cells decrease HFHCD-induced tumor growth acceleration. Reverting the HFHCD to a chow diet at the time of tumor implantation protects against tumor growth. Together, these data shed light on cross-disease communication between cardiovascular pathologies and cancer.
    DOI:  https://doi.org/10.1038/s41467-022-33034-0
  31. Lancet Healthy Longev. 2022 Mar;3(3): e194-e205
    Biological ageing with HIV infection: evaluating the geroscience hypothesis.
    Monty Montano, Krisann K Oursler, Ke Xu, Yan V Sun, Vincent C Marconi.
      Although people with HIV are living longer, as they age they remain disproportionately burdened with multimorbidity that is exacerbated in resource-poor settings. The geroscience hypothesis postulates that a discrete set of between five and ten hallmarks of biological ageing drive multimorbidity, but these processes have not been systematically examined in the context of people with HIV. We examine four major hallmarks of ageing (macromolecular damage, senescence, inflammation, and stem-cell dysfunction) as gerodrivers in the context of people with HIV. As a counterbalance, we introduce healthy ageing, physiological reserve, intrinsic capacity, and resilience as promoters of geroprotection that counteract gerodrivers. We discuss emerging geroscience-based diagnostic biomarkers and therapeutic strategies, and provide examples based on recent advances in cellular senescence, and other, non-pharmacological approaches. Finally, we present a conceptual model of biological ageing in the general population and in people with HIV that integrates gerodrivers and geroprotectors as modulators of homoeostatic reserves and organ function over the lifecourse.
    DOI:  https://doi.org/10.1016/s2666-7568(21)00278-6
  32. STAR Protoc. 2022 Sep 14. pii: S2666-1667(22)00557-3. [Epub ahead of print]3(4): 101677
    Detection of m6A RNA modifications at single-nucleotide resolution using m6A-selective allyl chemical labeling and sequencing.
    Yong Peng, Hanzhe Meng, Ruiqi Ge, Shun Liu, Mengjie Chen, Chuan He, Lulu Hu.
      As the most abundant internal mRNA modification, N6-methyladenosine (m6A) was involved in almost all the aspects of RNA metabolism. Here, we introduce our protocol for m6A-SAC-seq, which enables the whole transcriptome-wide mapping of m6A RNA modification at single-nucleotide resolution with stoichiometry information. m6A-SAC-seq relies on selective allyl labeling of m6A by specific methyltransferase and chemical treatment that introduce mutation upon reverse transcription. The technique only requires ∼30 ng of input RNA. For complete details on the use and execution of this protocol, please refer to Hu et al. (2022).
    Keywords:  Bioinformatics; Biotechnology and bioengineering; Chemistry; Genomics; Molecular biology; Molecular/Chemical probes; Protein biochemistry; Protein expression and purification; Sequence analysis
    DOI:  https://doi.org/10.1016/j.xpro.2022.101677
  33. Cell. 2022 Sep 15. pii: S0092-8674(22)01066-2. [Epub ahead of print]185(19): 3638-3638.e1
    SnapShot: Mechanotransduction in the nucleus.
    Fabien Bertillot, Yekaterina A Miroshnikova, Sara A Wickström.
      Cells are continuously exposed to tissue-specific extrinsic forces that are counteracted by cell-intrinsic force generation through the actomyosin cytoskeleton and alterations in the material properties of various cellular components, including the nucleus. Forces impact nuclei both directly through inducing deformation, which is sensed by various mechanosensitive components of the nucleus, as well as indirectly through the actomyosin cytoskeleton and mechanosensitive pathways activated in the cytoplasm. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2022.08.017
  34. Nature. 2022 Sep 14.
    Independent origins of fetal liver haematopoietic stem and progenitor cells.
    Tomomasa Yokomizo, Takako Ideue, Saori Morino-Koga, Cheng Yong Tham, Tomohiko Sato, Naoki Takeda, Yoshiaki Kubota, Mineo Kurokawa, Norio Komatsu, Minetaro Ogawa, Kimi Araki, Motomi Osato, Toshio Suda.
      Self-renewal and differentiation are tightly controlled to maintain haematopoietic stem cell (HSC) homeostasis in the adult bone marrow1,2. During fetal development, expansion of HSCs (self-renewal) and production of differentiated haematopoietic cells (differentiation) are both required to sustain the haematopoietic system for body growth3,4. However, it remains unclear how these two seemingly opposing tasks are accomplished within the short embryonic period. Here we used in vivo genetic tracing in mice to analyse the formation of HSCs and progenitors from intra-arterial haematopoietic clusters, which contain HSC precursors and express the transcription factor hepatic leukaemia factor (HLF). Through kinetic study, we observed the simultaneous formation of HSCs and defined progenitors-previously regarded as descendants of HSCs5-from the HLF+ precursor population, followed by prompt formation of the hierarchical haematopoietic population structure in the fetal liver in an HSC-independent manner. The transcription factor EVI1 is heterogeneously expressed within the precursor population, with EVI1hi cells being predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs. By genetically manipulating EVI1 expression, we were able to alter HSC and progenitor output from precursors in vivo. Using fate tracking, we also demonstrated that fetal HSCs are slowly used to produce short-term HSCs at late gestation. These data suggest that fetal HSCs minimally contribute to the generation of progenitors and functional blood cells before birth. Stem cell-independent pathways during development thus offer a rational strategy for the rapid and simultaneous growth of tissues and stem cell pools.
    DOI:  https://doi.org/10.1038/s41586-022-05203-0
  35. Nat Commun. 2022 Sep 12. 13(1): 5351
    GCAF(TMEM251) regulates lysosome biogenesis by activating the mannose-6-phosphate pathway.
    Weichao Zhang, Xi Yang, Yingxiang Li, Linchen Yu, Bokai Zhang, Jianchao Zhang, Woo Jung Cho, Varsha Venkatarangan, Liang Chen, Bala Bharathi Burugula, Sarah Bui, Yanzhuang Wang, Cunming Duan, Jacob O Kitzman, Ming Li.
      The mannose-6-phosphate (M6P) biosynthetic pathway for lysosome biogenesis has been studied for decades and is considered a well-understood topic. However, whether this pathway is regulated remains an open question. In a genome-wide CRISPR/Cas9 knockout screen, we discover TMEM251 as the first regulator of the M6P modification. Deleting TMEM251 causes mistargeting of most lysosomal enzymes due to their loss of M6P modification and accumulation of numerous undigested materials. We further demonstrate that TMEM251 localizes to the Golgi and is required for the cleavage and activity of GNPT, the enzyme that catalyzes M6P modification. In zebrafish, TMEM251 deletion leads to severe developmental defects including heart edema and skeletal dysplasia, which phenocopies Mucolipidosis Type II. Our discovery provides a mechanism for the newly discovered human disease caused by TMEM251 mutations. We name TMEM251 as GNPTAB cleavage and activity factor (GCAF) and its related disease as Mucolipidosis Type V.
    DOI:  https://doi.org/10.1038/s41467-022-33025-1
  36. Immunity. 2022 Sep 13. pii: S1074-7613(22)00395-8. [Epub ahead of print]55(9): 1515-1529
    Liver macrophages in health and disease.
    Martin Guilliams, Charlotte L Scott.
      Single-cell and spatial transcriptomic technologies have revealed an underappreciated heterogeneity of liver macrophages. This has led us to rethink the involvement of macrophages in liver homeostasis and disease. Identification of conserved gene signatures within these cells across species and diseases is enabling the correct identification of specific macrophage subsets and the generation of more specific tools to track and study the functions of these cells. Here, we discuss what is currently known about the definitions of these different macrophage populations, the markers that can be used to identify them, how they are wired within the liver, and their functional specializations in health and disease.
    Keywords:  Kupffer cells; LAMs; NASH; integrated niche; lipid-associated macrophages; liver disease; liver homeostasis; liver macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2022.08.002
  37. J Exp Med. 2022 Oct 03. pii: e20220094. [Epub ahead of print]219(10):
    Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.
    Masato Ogishi, Andrés Augusto Arias, Rui Yang, Ji Eun Han, Peng Zhang, Darawan Rinchai, Joshua Halpern, Jeanette Mulwa, Narelle Keating, Maya Chrabieh, Candice Lainé, Yoann Seeleuthner, Noé Ramírez-Alejo, Nioosha Nekooie-Marnany, Andrea Guennoun, Ingrid Muller-Fleckenstein, Bernhard Fleckenstein, Sara S Kilic, Yoshiyuki Minegishi, Stephan Ehl, Petra Kaiser-Labusch, Yasemin Kendir-Demirkol, Flore Rozenberg, Abderrahmane Errami, Shen-Ying Zhang, Qian Zhang, Jonathan Bohlen, Quentin Philippot, Anne Puel, Emmanuelle Jouanguy, Zahra Pourmoghaddas, Shahrzad Bakhtiar, Andre M Willasch, Gerd Horneff, Genevieve Llanora, Lynette P Shek, Louis Y A Chai, Sen Hee Tay, Hamid H Rahimi, Seyed Alireza Mahdaviani, Serdar Nepesov, Aziz A Bousfiha, Emine Hafize Erdeniz, Adem Karbuz, Nico Marr, Carmen Navarrete, Mehdi Adeli, Lennart Hammarstrom, Hassan Abolhassani, Nima Parvaneh, Saleh Al Muhsen, Mohammed F Alosaimi, Fahad Alsohime, Maryam Nourizadeh, Mostafa Moin, Rand Arnaout, Saad Alshareef, Jamila El-Baghdadi, Ferah Genel, Roya Sherkat, Ayça Kiykim, Esra Yücel, Sevgi Keles, Jacinta Bustamante, Laurent Abel, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis.
      Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
    DOI:  https://doi.org/10.1084/jem.20220094
  38. Nature. 2022 Sep 14.
    Glucose-driven TOR-FIE-PRC2 signalling controls plant development.
    Ruiqiang Ye, Meiyue Wang, Hao Du, Shweta Chhajed, Jin Koh, Kun-Hsiang Liu, Jinwoo Shin, Yue Wu, Lin Shi, Lin Xu, Sixue Chen, Yijing Zhang, Jen Sheen.
      Nutrients and energy have emerged as central modulators of developmental programmes in plants and animals1-3. The evolutionarily conserved target of rapamycin (TOR) kinase is a master integrator of nutrient and energy signalling that controls growth. Despite its key regulatory roles in translation, proliferation, metabolism and autophagy2-5, little is known about how TOR shapes developmental transitions and differentiation. Here we show that glucose-activated TOR kinase controls genome-wide histone H3 trimethylation at K27 (H3K27me3) in Arabidopsis thaliana, which regulates cell fate and development6-10. We identify FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), an indispensable component of Polycomb repressive complex 2 (PRC2), which catalyses H3K27me3 (refs. 6-8,10-12), as a TOR target. Direct phosphorylation by TOR promotes the dynamic translocation of FIE from the cytoplasm to the nucleus. Mutation of the phosphorylation site on FIE abrogates the global H3K27me3 landscape, reprogrammes the transcriptome and disrupts organogenesis in plants. Moreover, glucose-TOR-FIE-PRC2 signalling modulates vernalization-induced floral transition. We propose that this signalling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem cell destiny in shoot and root meristems and control leaf, flower and silique patterning, branching and vegetative-to-reproduction transition. Our findings reveal a fundamental mechanism of nutrient signalling in direct epigenome reprogramming, with broad relevance for the developmental control of multicellular organisms.
    DOI:  https://doi.org/10.1038/s41586-022-05171-5
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