bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒10‒15
39 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A quest into the human brain.
  2. Apoptotic stress causes mtDNA release during senescence and drives the SASP.
  3. Illuminating the human yolk sac through single-cell omics.
  4. People.
  5. ERMAP activates phagocytosis in Kupffer cells to restrict liver metastases.
  6. SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
  7. The distinctive immune features of long COVID.
  8. A family portrait of human brain cells.
  9. Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
  10. Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release.
  11. Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.
  12. Gene-by-environment regulation of Kupffer cell transcriptomes and epigenomes.
  13. Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.
  14. Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
  15. Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells.
  16. FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
  17. Unaltered hepatic wound healing response in male rats with ancestral liver injury.
  18. Structure of native chromatin fibres revealed by Cryo-ET in situ.
  19. Exporting longevity adaptations.
  20. Age-dependent topic modeling of comorbidities in UK Biobank identifies disease subtypes with differential genetic risk.
  21. Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.
  22. Bone-derived PDGF-BB drives brain vascular calcification in male mice.
  23. COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
  24. Identifying genetic subtypes of disease from hospital diagnosis records.
  25. Neuronal chromatin meta-domains.
  26. This is the largest map of the human brain ever made.
  27. MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression.
  28. A single-cell multi-omic atlas spanning the adult rhesus macaque brain.
  29. An adrenaline kick to exhaust T cells.
  30. Anti-obesity drugs' side effects: what we know so far.
  31. Structural basis of dimerization of chemokine receptors CCR5 and CXCR4.
  32. Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.
  33. Monitoring protein proximity with fluorogens.
  34. Structure of the transcription open complex of distinct σI factors.
  35. HMGA2 directly mediates chromatin condensation in association with neuronal fate regulation.
  36. Why BMI is flawed - and how to redefine obesity.
  37. MOF moves into mitochondria.
  38. Tbx1 orchestrates an immune niche that safeguards a broken heart.
  39. UV-B irradiation-activated E3 ligase GmILPA1 modulates gibberellin catabolism to increase plant height in soybean.
  1. Science. 2023 Oct 13. 382(6667): 166-167
    A quest into the human brain.
    Mattia Maroso.
      
    DOI:  https://doi.org/10.1126/science.adl0913
  2. Nature. 2023 Oct 11.
    Apoptotic stress causes mtDNA release during senescence and drives the SASP.
    Stella Victorelli, Hanna Salmonowicz, James Chapman, Helene Martini, Maria Grazia Vizioli, Joel S Riley, Catherine Cloix, Ella Hall-Younger, Jair Machado Espindola-Netto, Diana Jurk, Anthony B Lagnado, Lilian Sales Gomez, Joshua N Farr, Dominik Saul, Rebecca Reed, George Kelly, Madeline Eppard, Laura C Greaves, Zhixun Dou, Nicholas Pirius, Karolina Szczepanowska, Rebecca A Porritt, Huijie Huang, Timothy Y Huang, Derek A Mann, Claudio Akio Masuda, Sundeep Khosla, Haiming Dai, Scott H Kaufmann, Emmanouil Zacharioudakis, Evripidis Gavathiotis, Nathan K LeBrasseur, Xue Lei, Alva G Sainz, Viktor I Korolchuk, Peter D Adams, Gerald S Shadel, Stephen W G Tait, João F Passos.
      Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP)1. Mitochondria are major regulators of the SASP; however, the underlying mechanisms have not been elucidated2. Mitochondria are often essential for apoptosis, a cell fate distinct from cellular senescence. During apoptosis, widespread mitochondrial outer membrane permeabilization (MOMP) commits a cell to die3. Here we find that MOMP occurring in a subset of mitochondria is a feature of cellular senescence. This process, called minority MOMP (miMOMP), requires BAX and BAK macropores enabling the release of mitochondrial DNA (mtDNA) into the cytosol. Cytosolic mtDNA in turn activates the cGAS-STING pathway, a major regulator of the SASP. We find that inhibition of MOMP in vivo decreases inflammatory markers and improves healthspan in aged mice. Our results reveal that apoptosis and senescence are regulated by similar mitochondria-dependent mechanisms and that sublethal mitochondrial apoptotic stress is a major driver of the SASP. We provide proof-of-concept that inhibition of miMOMP-induced inflammation may be a therapeutic route to improve healthspan.
    DOI:  https://doi.org/10.1038/s41586-023-06621-4
  3. Nat Rev Immunol. 2023 Oct 09.
    Illuminating the human yolk sac through single-cell omics.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-023-00957-8
  4. Nat Biotechnol. 2023 Oct;41(10): 1488
    People.
      
    DOI:  https://doi.org/10.1038/s41587-023-01975-6
  5. Nat Immunol. 2023 Oct 09.
    ERMAP activates phagocytosis in Kupffer cells to restrict liver metastases.
      
    DOI:  https://doi.org/10.1038/s41590-023-01647-2
  6. Nat Commun. 2023 Oct 12. 14(1): 6416
    SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.
    Shi Jiao, Chuanchuan Li, Fenghua Guo, Jinjin Zhang, Hui Zhang, Zhifa Cao, Wenjia Wang, Wenbo Bu, Mobin Lin, Junhong Lü, Zhaocai Zhou.
      Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-βTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.
    DOI:  https://doi.org/10.1038/s41467-023-42187-5
  7. Nat Rev Immunol. 2023 Oct 10.
    The distinctive immune features of long COVID.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-023-00958-7
  8. Science. 2023 Oct 13. 382(6667): 168-169
    A family portrait of human brain cells.
    Alyssa Weninger, Paola Arlotta.
      A cell census provides information on the source of human brain specialization.
    DOI:  https://doi.org/10.1126/science.adk4857
  9. EMBO Rep. 2023 Oct 11. e57228
    Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.
    Conor T Ronayne, Thomas D Jackson, Christopher F Bennett, Elizabeth A Perry, Noa Kantorovic, Pere Puigserver.
      Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.
    Keywords:  IRE1α; MALSU1; mitochondrial disease; mitoribosome; tetracyclines
    DOI:  https://doi.org/10.15252/embr.202357228
  10. Nat Commun. 2023 Oct 09. 14(1): 6322
    Polarized microtubule remodeling transforms the morphology of reactive microglia and drives cytokine release.
    Max Adrian, Martin Weber, Ming-Chi Tsai, Caspar Glock, Olga I Kahn, Lilian Phu, Tommy K Cheung, William J Meilandt, Christopher M Rose, Casper C Hoogenraad.
      Microglial reactivity is a pathological hallmark in many neurodegenerative diseases. During stimulation, microglia undergo complex morphological changes, including loss of their characteristic ramified morphology, which is routinely used to detect and quantify inflammation in the brain. However, the underlying molecular mechanisms and the relation between microglial morphology and their pathophysiological function are unknown. Here, proteomic profiling of lipopolysaccharide (LPS)-reactive microglia identifies microtubule remodeling pathways as an early factor that drives the morphological change and subsequently controls cytokine responses. We find that LPS-reactive microglia reorganize their microtubules to form a stable and centrosomally-anchored array to facilitate efficient cytokine trafficking and release. We identify cyclin-dependent kinase 1 (Cdk-1) as a critical upstream regulator of microtubule remodeling and morphological change in-vitro and in-situ. Cdk-1 inhibition also rescues tau and amyloid fibril-induced morphology changes. These results demonstrate a critical role for microtubule dynamics and reorganization in microglial reactivity and modulating cytokine-mediated inflammatory responses.
    DOI:  https://doi.org/10.1038/s41467-023-41891-6
  11. Nat Commun. 2023 10 10. 14(1): 6330
    Kupffer cells prevent pancreatic ductal adenocarcinoma metastasis to the liver in mice.
    Stacy K Thomas, Max M Wattenberg, Shaanti Choi-Bose, Mark Uhlik, Ben Harrison, Heather Coho, Christopher R Cassella, Meredith L Stone, Dhruv Patel, Kelly Markowitz, Devora Delman, Michael Chisamore, Jeremy Drees, Nandita Bose, Gregory L Beatty.
      Although macrophages contribute to cancer cell dissemination, immune evasion, and metastatic outgrowth, they have also been reported to coordinate tumor-specific immune responses. We therefore hypothesized that macrophage polarization could be modulated therapeutically to prevent metastasis. Here, we show that macrophages respond to β-glucan (odetiglucan) treatment by inhibiting liver metastasis. β-glucan activated liver-resident macrophages (Kupffer cells), suppressed cancer cell proliferation, and invoked productive T cell-mediated responses against liver metastasis in pancreatic cancer mouse models. Although excluded from metastatic lesions, Kupffer cells were critical for the anti-metastatic activity of β-glucan, which also required T cells. Furthermore, β-glucan drove T cell activation and macrophage re-polarization in liver metastases in mice and humans and sensitized metastatic lesions to anti-PD1 therapy. These findings demonstrate the significance of macrophage function in metastasis and identify Kupffer cells as a potential therapeutic target against pancreatic cancer metastasis to the liver.
    DOI:  https://doi.org/10.1038/s41467-023-41771-z
  12. Nat Immunol. 2023 Oct 12.
    Gene-by-environment regulation of Kupffer cell transcriptomes and epigenomes.
      
    DOI:  https://doi.org/10.1038/s41590-023-01643-6
  13. Nat Immunol. 2023 Oct 12.
    Targeting PGLYRP1 promotes antitumor immunity while inhibiting autoimmune neuroinflammation.
    Alexandra Schnell, Linglin Huang, Brianna M L Regan, Vasundhara Singh, Dominik Vonficht, Alina Bollhagen, Mona Wang, Yu Hou, Lloyd Bod, Raymond A Sobel, Norio Chihara, Asaf Madi, Ana C Anderson, Aviv Regev, Vijay K Kuchroo.
      Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.
    DOI:  https://doi.org/10.1038/s41590-023-01645-4
  14. Nat Commun. 2023 Oct 11. 14(1): 6383
    Glucocerebrosidase mutations disrupt the lysosome and now the mitochondria.
    Andrés D Klein, Tiago Fleming Outeiro.
      
    DOI:  https://doi.org/10.1038/s41467-023-42107-7
  15. Nat Commun. 2023 Oct 12. 14(1): 6412
    Perinatal murine cytomegalovirus infection reshapes the transcriptional profile and functionality of NK cells.
    Carmen Rožmanić, Berislav Lisnić, Marina Pribanić Matešić, Andrea Mihalić, Lea Hiršl, Eugene Park, Ana Lesac Brizić, Daniela Indenbirken, Ina Viduka, Marina Šantić, Barbara Adler, Wayne M Yokoyama, Astrid Krmpotić, Vanda Juranić Lisnić, Stipan Jonjić, Ilija Brizić.
      Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA Ifng-as1 expression. Moreover, the bone marrow's capacity to efficiently generate new NK cells is reduced, explaining the prolonged negative effects of perinatal infection on NK cells. This study demonstrates that viral infections in early life can profoundly impact NK cell biology, including long-lasting impairment in NK cell functionality.
    DOI:  https://doi.org/10.1038/s41467-023-42182-w
  16. Nat Commun. 2023 10 10. 14(1): 6344
    FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes.
    Jiamin Qiu, Feng Yue, Peipei Zhu, Jingjuan Chen, Fan Xu, Lijia Zhang, Kun Ho Kim, Madigan M Snyder, Nanjian Luo, Hao-Wei Xu, Fang Huang, W Andy Tao, Shihuan Kuang.
      Cold stimulation dynamically remodels mitochondria in brown adipose tissue (BAT) to facilitate non-shivering thermogenesis in mammals, but what regulates mitochondrial plasticity is poorly understood. Comparing mitochondrial proteomes in response to cold revealed FAM210A as a cold-inducible mitochondrial inner membrane protein. An adipocyte-specific constitutive knockout of Fam210a (Fam210aAKO) disrupts mitochondrial cristae structure and diminishes the thermogenic activity of BAT, rendering the Fam210aAKO mice vulnerable to lethal hypothermia under acute cold exposure. Induced knockout of Fam210a in adult adipocytes (Fam210aiAKO) does not affect steady-state mitochondrial structure under thermoneutrality, but impairs cold-induced mitochondrial remodeling, leading to progressive loss of cristae and reduction of mitochondrial density. Proteomics reveals an association between FAM210A and OPA1, whose cleavage governs cristae dynamics and mitochondrial remodeling. Mechanistically, FAM210A interacts with mitochondrial protease YME1L and modulates its activity toward OMA1 and OPA1 cleavage. These data establish FAM210A as a key regulator of mitochondrial cristae remodeling in BAT and shed light on the mechanism underlying mitochondrial plasticity in response to cold.
    DOI:  https://doi.org/10.1038/s41467-023-41988-y
  17. Nat Commun. 2023 10 10. 14(1): 6353
    Unaltered hepatic wound healing response in male rats with ancestral liver injury.
    Johanna Beil, Juliane Perner, Lena Pfaller, Marie-Apolline Gérard, Alessandro Piaia, Arno Doelemeyer, Adi Wasserkrug Naor, Lori Martin, Aline Piequet, Valérie Dubost, Salah-Dine Chibout, Jonathan Moggs, Rémi Terranova.
      The possibility that ancestral environmental exposure could result in adaptive inherited effects in mammals has been long debated. Numerous rodent models of transgenerational responses to various environmental factors have been published but due to technical, operational and resource burden, most still await independent confirmation. A previous study reported multigenerational epigenetic adaptation of the hepatic wound healing response upon exposure to the hepatotoxicant carbon tetrachloride (CCl4) in male rats. Here, we comprehensively investigate the transgenerational effects by repeating the original CCl4 multigenerational study with increased power, pedigree tracing, F2 dose-response and suitable randomization schemes. Detailed pathology evaluations do not support adaptive phenotypic suppression of the hepatic wound healing response or a greater fitness of F2 animals with ancestral liver injury exposure. However, transcriptomic analyses identified genes whose expression correlates with ancestral liver injury, although the biological relevance of this apparent transgenerational transmission at the molecular level remains to be determined. This work overall highlights the need for independent evaluation of transgenerational epigenetic inheritance paradigms in mammals.
    DOI:  https://doi.org/10.1038/s41467-023-41998-w
  18. Nat Commun. 2023 10 10. 14(1): 6324
    Structure of native chromatin fibres revealed by Cryo-ET in situ.
    Zhen Hou, Frank Nightingale, Yanan Zhu, Craig MacGregor-Chatwin, Peijun Zhang.
      The structure of chromatin plays pivotal roles in regulating gene transcription, DNA replication and repair, and chromosome segregation. This structure, however, remains elusive. Here, using cryo-FIB and cryo-ET, we delineate the 3D architecture of native chromatin fibres in intact interphase human T-lymphoblasts and determine the in situ structures of nucleosomes in different conformations. These chromatin fibres are not structured as uniform 30 nm one-start or two-start filaments but are composed of relaxed, variable zigzag organizations of nucleosomes connected by straight linker DNA. Nucleosomes with little H1 and linker DNA density are distributed randomly without any spatial preference. This work will inspire future high-resolution investigations on native chromatin structures in situ at both a single-nucleosome level and a population level under many different cellular conditions in health and disease.
    DOI:  https://doi.org/10.1038/s41467-023-42072-1
  19. Nat Aging. 2023 Oct;3(10): 1176
    Exporting longevity adaptations.
    Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-023-00507-w
  20. Nat Genet. 2023 Oct 09.
    Age-dependent topic modeling of comorbidities in UK Biobank identifies disease subtypes with differential genetic risk.
    Xilin Jiang, Martin Jinye Zhang, Yidong Zhang, Arun Durvasula, Michael Inouye, Chris Holmes, Alkes L Price, Gil McVean.
      The analysis of longitudinal data from electronic health records (EHRs) has the potential to improve clinical diagnoses and enable personalized medicine, motivating efforts to identify disease subtypes from patient comorbidity information. Here we introduce an age-dependent topic modeling (ATM) method that provides a low-rank representation of longitudinal records of hundreds of distinct diseases in large EHR datasets. We applied ATM to 282,957 UK Biobank samples, identifying 52 diseases with heterogeneous comorbidity profiles; analyses of 211,908 All of Us samples produced concordant results. We defined subtypes of the 52 heterogeneous diseases based on their comorbidity profiles and compared genetic risk across disease subtypes using polygenic risk scores (PRSs), identifying 18 disease subtypes whose PRS differed significantly from other subtypes of the same disease. We further identified specific genetic variants with subtype-dependent effects on disease risk. In conclusion, ATM identifies disease subtypes with differential genome-wide and locus-specific genetic risk profiles.
    DOI:  https://doi.org/10.1038/s41588-023-01522-8
  21. J Clin Invest. 2023 Oct 12. pii: e173160. [Epub ahead of print]
    Endothelial lipid droplets suppress eNOS to link high fat consumption to blood pressure elevation.
    Boa Kim, Wencao Zhao, Soon Yew Tang, Michael G Levin, Ayon Ibrahim, Yifan Yang, Emilia M Roberts, Ling Lai, Jian Li, Richard K Assoian, Garret A FitzGerald, Zoltan Arany.
      The metabolic syndrome, today affecting more than 20% of the US population, is a group of five conditions that often co-exist and that strongly predispose to cardiovascular disease. How these conditions are linked mechanistically remains unclear, especially two of these: obesity and elevated blood pressure. Here we show that high fat consumption in mice leads to the accumulation of lipid droplets in endothelial cells throughout the organism, and that lipid droplet accumulation in endothelium suppresses endothelial nitric oxide synthase (eNOS), reduces NO production, elevates blood pressure, and accelerates atherosclerosis. Mechanistically, the accumulation of lipid droplets destabilizes eNOS mRNA and activates an endothelial inflammatory signaling cascade that suppresses eNOS and NO production. Pharmacological prevention of lipid droplet formation reverses the suppression of NO production in cell culture and in vivo, and blunts blood pressure elevation in response to high fat diet. These results highlight lipid droplets as a critical and unappreciated component of endothelial cell biology, explain how lipids increase blood pressure acutely, and provide a mechanistic account for the epidemiological link between obesity and elevated blood pressure.
    Keywords:  Cardiology; Endothelial cells
    DOI:  https://doi.org/10.1172/JCI173160
  22. J Clin Invest. 2023 Oct 10. pii: e168447. [Epub ahead of print]
    Bone-derived PDGF-BB drives brain vascular calcification in male mice.
    Jiekang Wang, Ching-Lien Fang, Kathleen Noller, Zhiliang Wei, Guanqiao Liu, Ke Shen, Kangping Song, Xu Cao, Mei Wan.
      Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large vessel calcifications in peripheral tissue is well-studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contribute to cerebrovascular calcification in male mice. Aged male mice exhibited higher serum PDGF-BB levels and a significantly higher incidence of brain calcification compared to young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevation of serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA sequencing revealed that PDGF-BB upregulates multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (pPDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of the osteoblast differentiation genes in pericytes and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induces brain vascular calcification by activating the pPDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.
    Keywords:  Bone Biology; Microcirculation; Neurological disorders; Osteoclast/osteoblast biology; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI168447
  23. Nat Metab. 2023 Oct 09.
    COX17 acetylation via MOF-KANSL complex promotes mitochondrial integrity and function.
    Sukanya Guhathakurta, Niyazi Umut Erdogdu, Juliane J Hoffmann, Iga Grzadzielewska, Alexander Schendzielorz, Janine Seyfferth, Christoph U Mårtensson, Mauro Corrado, Adam Karoutas, Bettina Warscheid, Nikolaus Pfanner, Thomas Becker, Asifa Akhtar.
      Reversible acetylation of mitochondrial proteins is a regulatory mechanism central to adaptive metabolic responses. Yet, how such functionally relevant protein acetylation is achieved remains unexplored. Here we reveal an unprecedented role of the MYST family lysine acetyltransferase MOF in energy metabolism via mitochondrial protein acetylation. Loss of MOF-KANSL complex members leads to mitochondrial defects including fragmentation, reduced cristae density and impaired mitochondrial electron transport chain complex IV integrity in primary mouse embryonic fibroblasts. We demonstrate COX17, a complex IV assembly factor, as a bona fide acetylation target of MOF. Loss of COX17 or expression of its non-acetylatable mutant phenocopies the mitochondrial defects observed upon MOF depletion. The acetylation-mimetic COX17 rescues these defects and maintains complex IV activity even in the absence of MOF, suggesting an activatory role of mitochondrial electron transport chain protein acetylation. Fibroblasts from patients with MOF syndrome who have intellectual disability also revealed respiratory defects that could be restored by alternative oxidase, acetylation-mimetic COX17 or mitochondrially targeted MOF. Overall, our findings highlight the critical role of MOF-KANSL complex in mitochondrial physiology and provide new insights into MOF syndrome.
    DOI:  https://doi.org/10.1038/s42255-023-00904-w
  24. Nat Genet. 2023 Oct 09.
    Identifying genetic subtypes of disease from hospital diagnosis records.
      
    DOI:  https://doi.org/10.1038/s41588-023-01521-9
  25. Nat Genet. 2023 Oct;55(10): 1609
    Neuronal chromatin meta-domains.
    Tiago Faial.
      
    DOI:  https://doi.org/10.1038/s41588-023-01541-5
  26. Nature. 2023 Oct 12.
    This is the largest map of the human brain ever made.
    Gemma Conroy.
      
    Keywords:  Genomics; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-03192-2
  27. Commun Biol. 2023 Oct 11. 6(1): 1030
    MUC1-C intersects chronic inflammation with epigenetic reprogramming by regulating the set1a compass complex in cancer progression.
    Atrayee Bhattacharya, Atsushi Fushimi, Keyi Wang, Nami Yamashita, Yoshihiro Morimoto, Satoshi Ishikawa, Tatsuaki Daimon, Tao Liu, Song Liu, Mark D Long, Donald Kufe.
      Chronic inflammation promotes epigenetic reprogramming in cancer progression by pathways that remain unclear. The oncogenic MUC1-C protein is activated by the inflammatory NF-κB pathway in cancer cells. There is no known involvement of MUC1-C in regulation of the COMPASS family of H3K4 methyltransferases. We find that MUC1-C regulates (i) bulk H3K4 methylation levels, and (ii) the COMPASS SET1A/SETD1A and WDR5 genes by an NF-κB-mediated mechanism. The importance of MUC1-C in regulating the SET1A COMPASS complex is supported by the demonstration that MUC1-C and WDR5 drive expression of FOS, ATF3 and other AP-1 family members. In a feedforward loop, MUC1-C, WDR5 and AP-1 contribute to activation of genes encoding TRAF1, RELB and other effectors in the chronic NF-κB inflammatory response. We also show that MUC1-C, NF-κB, WDR5 and AP-1 are necessary for expression of the (i) KLF4 master regulator of the pluripotency network and (ii) NOTCH1 effector of stemness. In this way, MUC1-C/NF-κB complexes recruit SET1A/WDR5 and AP-1 to enhancer-like signatures in the KLF4 and NOTCH1 genes with increases in H3K4me3 levels, chromatin accessibility and transcription. These findings indicate that MUC1-C regulates the SET1A COMPASS complex and the induction of genes that integrate NF-κB-mediated chronic inflammation with cancer progression.
    DOI:  https://doi.org/10.1038/s42003-023-05395-9
  28. Sci Adv. 2023 Oct 13. 9(41): eadh1914
    A single-cell multi-omic atlas spanning the adult rhesus macaque brain.
    Cayo Biobank Research Unit
      Cataloging the diverse cellular architecture of the primate brain is crucial for understanding cognition, behavior, and disease in humans. Here, we generated a brain-wide single-cell multimodal molecular atlas of the rhesus macaque brain. Together, we profiled 2.58 M transcriptomes and 1.59 M epigenomes from single nuclei sampled from 30 regions across the adult brain. Cell composition differed extensively across the brain, revealing cellular signatures of region-specific functions. We also identified 1.19 M candidate regulatory elements, many previously unidentified, allowing us to explore the landscape of cis-regulatory grammar and neurological disease risk in a cell type-specific manner. Altogether, this multi-omic atlas provides an open resource for investigating the evolution of the human brain and identifying novel targets for disease interventions.
    DOI:  https://doi.org/10.1126/sciadv.adh1914
  29. Nat Immunol. 2023 Oct 09.
    An adrenaline kick to exhaust T cells.
    Jacqueline Berner, Dietmar Zehn.
      
    DOI:  https://doi.org/10.1038/s41590-023-01650-7
  30. Nature. 2023 Oct 13.
    Anti-obesity drugs' side effects: what we know so far.
    Mariana Lenharo.
      
    Keywords:  Medical research; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-023-03183-3
  31. Nat Commun. 2023 Oct 13. 14(1): 6439
    Structural basis of dimerization of chemokine receptors CCR5 and CXCR4.
    Daniele Di Marino, Paolo Conflitti, Stefano Motta, Vittorio Limongelli.
      G protein-coupled receptors (GPCRs) are prominent drug targets responsible for extracellular-to-intracellular signal transduction. GPCRs can form functional dimers that have been poorly characterized so far. Here, we show the dimerization mechanism of the chemokine receptors CCR5 and CXCR4 by means of an advanced free-energy technique named coarse-grained metadynamics. Our results reproduce binding events between the GPCRs occurring in the minute timescale, revealing a symmetric and an asymmetric dimeric structure for each of the three investigated systems, CCR5/CCR5, CXCR4/CXCR4, and CCR5/CXCR4. The transmembrane helices TM4-TM5 and TM6-TM7 are the preferred binding interfaces for CCR5 and CXCR4, respectively. The identified dimeric states differ in the access to the binding sites of the ligand and G protein, indicating that dimerization may represent a fine allosteric mechanism to regulate receptor activity. Our study offers structural basis for the design of ligands able to modulate the formation of CCR5 and CXCR4 dimers and in turn their activity, with therapeutic potential against HIV, cancer, and immune-inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-023-42082-z
  32. Nat Commun. 2023 Oct 09. 14(1): 6304
    Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis.
    Yuichi Tsuchiya, Takao Seki, Kenta Kobayashi, Sachiko Komazawa-Sakon, Shigeyuki Shichino, Takashi Nishina, Kyoko Fukuhara, Kenichi Ikejima, Hidenari Nagai, Yoshinori Igarashi, Satoshi Ueha, Akira Oikawa, Shinya Tsurusaki, Soh Yamazaki, Chiharu Nishiyama, Tetuo Mikami, Hideo Yagita, Ko Okumura, Taketomo Kido, Atsushi Miyajima, Kouji Matsushima, Mai Imasaka, Kimi Araki, Toru Imamura, Masaki Ohmuraya, Minoru Tanaka, Hiroyasu Nakano.
      Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat+ hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.
    DOI:  https://doi.org/10.1038/s41467-023-42058-z
  33. Nat Biotechnol. 2023 Oct;41(10): 1386
    Monitoring protein proximity with fluorogens.
    Alexandra Despang.
      
    DOI:  https://doi.org/10.1038/s41587-023-02000-6
  34. Nat Commun. 2023 Oct 13. 14(1): 6455
    Structure of the transcription open complex of distinct σI factors.
    Jie Li, Haonan Zhang, Dongyu Li, Ya-Jun Liu, Edward A Bayer, Qiu Cui, Yingang Feng, Ping Zhu.
      Bacterial σI factors of the σ70-family are widespread in Bacilli and Clostridia and are involved in the heat shock response, iron metabolism, virulence, and carbohydrate sensing. A multiplicity of σI paralogues in some cellulolytic bacteria have been shown to be responsible for the regulation of the cellulosome, a multienzyme complex that mediates efficient cellulose degradation. Here, we report two structures at 3.0 Å and 3.3 Å of two transcription open complexes formed by two σI factors, SigI1 and SigI6, respectively, from the thermophilic, cellulolytic bacterium, Clostridium thermocellum. These structures reveal a unique, hitherto-unknown recognition mode of bacterial transcriptional promoters, both with respect to domain organization and binding to promoter DNA. The key characteristics that determine the specificities of the σI paralogues were further revealed by comparison of the two structures. Consequently, the σI factors represent a distinct set of the σ70-family σ factors, thus highlighting the diversity of bacterial transcription.
    DOI:  https://doi.org/10.1038/s41467-023-41796-4
  35. Nat Commun. 2023 Oct 12. 14(1): 6420
    HMGA2 directly mediates chromatin condensation in association with neuronal fate regulation.
    Naohiro Kuwayama, Tomoya Kujirai, Yusuke Kishi, Rina Hirano, Kenta Echigoya, Lingyan Fang, Sugiko Watanabe, Mitsuyoshi Nakao, Yutaka Suzuki, Kei-Ichiro Ishiguro, Hitoshi Kurumizaka, Yukiko Gotoh.
      Identification of factors that regulate chromatin condensation is important for understanding of gene regulation. High-mobility group AT-hook (HMGA) proteins 1 and 2 are abundant nonhistone chromatin proteins that play a role in many biological processes including tissue stem-progenitor cell regulation, but the nature of their protein function remains unclear. Here we show that HMGA2 mediates direct condensation of polynucleosomes and forms droplets with nucleosomes. Consistently, most endogenous HMGA2 localized to transposase 5- and DNase I-inaccessible chromatin regions, and its binding was mostly associated with gene repression, in mouse embryonic neocortical cells. The AT-hook 1 domain was necessary for chromatin condensation by HMGA2 in vitro and in cellulo, and an HMGA2 mutant lacking this domain was defective in the ability to maintain neuronal progenitors in vivo. Intrinsically disordered regions of other proteins could substitute for the AT-hook 1 domain in promoting this biological function of HMGA2. Taken together, HMGA2 may regulate neural cell fate by its chromatin condensation activity.
    DOI:  https://doi.org/10.1038/s41467-023-42094-9
  36. Nature. 2023 Oct;622(7982): 232-233
    Why BMI is flawed - and how to redefine obesity.
    McKenzie Prillaman.
      
    Keywords:  Health care; Obesity; Public health
    DOI:  https://doi.org/10.1038/d41586-023-03143-x
  37. Nat Metab. 2023 Oct 09.
    MOF moves into mitochondria.
    Natalie Niemi.
      
    DOI:  https://doi.org/10.1038/s42255-023-00892-x
  38. Immunity. 2023 Oct 10. pii: S1074-7613(23)00413-2. [Epub ahead of print]56(10): 2177-2179
    Tbx1 orchestrates an immune niche that safeguards a broken heart.
    Sara Perrotta, Daniela Carnevale.
      Cardiac lymphatics cooperate with the reparative immune response in myocardial healing after infarction. In this issue of Immunity, Wang and colleagues discover a mechanism underlying this cooperation, dependent on the transcription factor Tbx1 and responsible for the creation of an immunosuppressive niche that mitigates autoimmunity.
    DOI:  https://doi.org/10.1016/j.immuni.2023.09.008
  39. Nat Commun. 2023 10 07. 14(1): 6262
    UV-B irradiation-activated E3 ligase GmILPA1 modulates gibberellin catabolism to increase plant height in soybean.
    Jiaqi Sun, Shiyu Huang, Qing Lu, Shuo Li, Shizhen Zhao, Xiaojian Zheng, Qian Zhou, Wenxiao Zhang, Jie Li, Lili Wang, Ke Zhang, Wenyu Zheng, Xianzhong Feng, Baohui Liu, Fanjiang Kong, Fengning Xiang.
      Plant height is a key agronomic trait that affects yield and is controlled by both phytohormone gibberellin (GA) and ultraviolet-B (UV-B) irradiation. However, whether and how plant height is modulated by UV-B-mediated changes in GA metabolism are not well understood. It has not been reported that the E3 ubiquitin ligase Anaphase Promoting Complex/Cyclosome (APC/C) is involved in the regulation of plant growth in response to environmental factors. We perform a forward genetic screen in soybean and find that a mutation in Glycine max Increased Leaf Petiole Angle1 (GmILPA1), encoding a subunit of the APC/C, lead to dwarfism under UV-B irradiation. UV-B promotes the accumulation of GmILPA1, which ubiquitinate the GA catabolic enzyme GA2 OXIDASE-like (GmGA2ox-like), resulting in its degradation in a UV-B-dependent manner. Another E3 ligase, GmUBL1, also ubiquitinate GmGA2ox-like and enhance the GmILPA1-mediated degradation of GmGA2ox-like, which suggest that GmILPA1-GmGA2ox-like module counteract the UV-B-mediated reduction of bioactive GAs. We also determine that GmILPA1 is a target of selection during soybean domestication and breeding. The deletion (Indel-665) in the promoter might facilitate the adaptation of soybean to high UV-B irradiation. This study indicates that an evolutionary GmILPA1 variant has the capability to develop ideal plant architecture with soybean cultivars.
    DOI:  https://doi.org/10.1038/s41467-023-41824-3
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