bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–11–16
nineteen papers selected by
Xiong Weng, University of Edinburgh
  1. Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis.
  2. The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
  3. YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis.
  4. Sirt6 prevents the age-related decline of H2S through the control of one-carbon metabolism.
  5. Adipocyte-derived extracellular vesicles are key regulators of central leptin sensitivity and energy homeostasis.
  6. Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
  7. Hepatocyte Piezo1 regulates glycogen metabolism via the FGF21-STAT3 pathway.
  8. Estimation and mapping of the missing heritability of human phenotypes.
  9. Glucocorticoid-induced changes of the gut microbiota and metabolic markers in healthy young men: Outcome of a randomized controlled trial.
  10. Termination of the integrated stress response.
  11. Lamin A/C regulates lipid metabolism and inflammation: insights from models of familial partial lipodystrophy 2.
  12. iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
  13. Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation.
  14. Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age-Associated Metabolic Abnormalities.
  15. Somatic mutations at scale.
  16. Alternative start codon selection shapes mitochondrial function and rare human diseases.
  17. A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.
  18. Unlocking rejuvenating potential of mesenchymal progenitor cells.
  19. Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
  1. Nat Commun. 2025 Nov 13. 16(1): 9973
    Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis.
    Yuanhua Qin, Wenjun Wu, Kequan Lin, Anthony J Davis, Yaping Huang.
      Dysregulation of heat shock protein DNAJA2 induces genomic instability and was consequently hypothesized to promote tumorigenesis. However, DNAJA2 knockout mice do not develop cancer but exhibit neonatal lethality and the underlying mechanism remains unknown. Here, we demonstrate that DNAJA2 maintains homeostatic glucose metabolism by regulating insulin signaling. Mechanistically, DNAJA2 binds to the insulin receptor (IR) and prevents adaptor protein 2 (AP2)-mediated spontaneous IR endocytosis by inhibiting the IR-AP2 interaction. Thus, DNAJA2 defects lead to reduced IR localization on the plasma membrane and suppression of the insulin-stimulated signaling cascade, thereby inhibiting glycogen synthesis and storage in the liver during embryogenesis, further resulting in neonatal lethality of DNAJA2-deficient mice. Analysis of public datasets reveals a strong association between DNAJA2 and metabolic phenotypes, including type 2 diabetes mellitus (T2DM) and obesity, in both humans and mice. In conclusion, our study elucidates the mechanism by which DNAJA2 regulates IR endocytosis, insulin signaling and glucose metabolism, shedding light on the pathogenesis of metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-64948-0
  2. Sci Adv. 2025 Nov 14. 11(46): eaea4660
    The bottleneck for maternal transmission of mtDNA is linked to purifying selection by autophagy.
    Laura S Kremer, Zoe Golder, Tom Barton-Owen, Polyxeni Papadea, Camilla Koolmeister, Patrick F Chinnery, Nils-Göran Larsson.
      Mammalian mitochondrial DNA (mtDNA) inheritance differs fundamentally from nuclear inheritance owing to exclusive maternal transmission, high mutation rate, and lack of recombination. Two key mechanisms shape this inheritance: the bottleneck, which drives stochastic transmission of maternal mtDNA variants, and purifying selection, which actively removes mutant mtDNA. Whether these mechanisms interact has been unresolved. To address this question, we generated a series of mouse models with random mtDNA mutations alongside alleles altering mtDNA copy number or decreasing autophagy. We demonstrate that tightening the mtDNA bottleneck increases heteroplasmic variance between individuals, causing lower mutational burden and nonsynonymous-to-synonymous ratios. In contrast, reduced autophagy weakens purifying selection, leading to decreased interoffspring heteroplasmic variance and increased mutational burden with higher nonsynonymous-to-synonymous ratios. These findings provide experimental evidence that the mtDNA bottleneck size modulates the efficacy of purifying selection. Our findings yield fundamental insights into the processes governing mammalian mtDNA transmission with direct implications for the origin and propagation of mtDNA mutations causing human disease.
    DOI:  https://doi.org/10.1126/sciadv.aea4660
  3. Nat Commun. 2025 Nov 12. 16(1): 9946
    YTHDF2 regulates self non-coding RNA metabolism to control inflammation and tumorigenesis.
    Seungwon Yang, Yan-Hong Cui, Haixia Li, Jiangbo Wei, Gayoung Park, Ming Sun, Michelle Verghese, Emma Wilkinson, Teresa Nam, Linnea Louise Lungstrom, Xiaolong Cui, Tae Young Ryu, Jing Chen, Marc Bissonnette, Chuan He, Yu-Ying He.
      The role of m6A RNA methylation of self non-coding RNA remains poorly understood. Here we show that m6A-methylated self U6 snRNA is recognized by YTHDF2 to reduce its stability and prevent its binding to Toll-like receptor 3 (TLR3), leading to decreased inflammatory responses in human and mouse cells and mouse models. At the molecular level, endosomal U6 snRNA binds to the LRR21 domain in TLR3, independent of m6A methylation, to activate inflammatory gene expression, a mechanism that is distinct from that of the best known synthetic TLR3 agonist poly I:C. Both U6 snRNA and YTHDF2 are localized to endosomes via the transmembrane protein SIDT2, where YTHDF2 functions to prevent the U6-TLR3 interaction. We further show that UVB exposure inhibits YTHDF2 by inducing its dephosphorylation and autophagic protein degradation in human keratinocytes and mouse skin. Skin-specific deletion of Ythdf2 in mice enhanced the UVB-induced skin inflammatory response and promoted tumor initiation. Taken together, our findings demonstrate that YTHDF2 plays a crucial role in controlling inflammation by inhibiting m6A U6-mediated TLR3 activation, suggesting that YTHDF2 and m6A U6 are potential therapeutic targets for preventing and treating inflammation and tumorigenesis.
    DOI:  https://doi.org/10.1038/s41467-025-64898-7
  4. Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2514084122
    Sirt6 prevents the age-related decline of H2S through the control of one-carbon metabolism.
    Noga Touitou, Liat Nahum, Sarit Feldman-Trabelsi, Matan Y Avivi, Miguel A Aon, Shoshana Naiman, Moran Rathaus, Asaf A Gertler, Asael Roichman, Lia Berkman Dvir, Michel Bernier, Nirad Banskota, Lir Beck, Ron Nagar, Zacharia Schwartz, Nathan L Price, Michal Harel, Batia Lerrer, Isao Ishii, Hanoch Senderowitz, Ruin Moaddel, Tamar Geiger, Rafael de Cabo, Haim Y Cohen.
      Mice overexpressing Sirt6 or fed a caloric restriction (CR) diet live longer with improved health. CR increases Sirt6 levels, and its beneficial effects are mediated by the gasotransmitter H2S, a one-carbon pathway product. Yet, the role of this pathway in Sirt6-regulated longevity remains elusive. Here, we show that Sirt6 controls hepatic one-carbon metabolism, preventing the aging-dependent H2S reduction, and the elevation of the methyl donor, S-adenosylmethionine (SAM). Sirt6 downregulates Slc7a11 expression in an Sp1-dependent manner, decreasing cystine uptake and increasing Cgl H2S production activity. Additionally, comparative acetylome in old livers revealed Sirt6-related differential acetylation of most of the one-carbon enzymes. Specifically, Sirt6-dependent Matα1 K235 deacetylation reduces its SAM production activity and Cbs binding, thereby reducing its activation of Cbs-dependent H2S production. The net outcome is H2S and SAM levels as observed in young animals. Thus, we unveil a fundamental mechanism for the promotion of healthy longevity by Sirt6.
    Keywords:  H2S; SIRT6; acetylation; aging; one carbon pathway
    DOI:  https://doi.org/10.1073/pnas.2514084122
  5. Cell Metab. 2025 Nov 11. pii: S1550-4131(25)00439-5. [Epub ahead of print]
    Adipocyte-derived extracellular vesicles are key regulators of central leptin sensitivity and energy homeostasis.
    Jin Wang, Xuhong Zhang, Ye Zhu, Haixiang Sun, Xuetao Chen, Zhicong Zhao, Nina Zhang, Chenyu Zhang, Liang Li, Yan Bi.
      The exact mechanisms underlying leptin resistance, the central mechanism of obesity, remain elusive. Herein, we demonstrate that adipocyte-derived extracellular vesicles (Ad-EVs) serve as key regulatory factors of hypothalamic circuits governing food intake and body weight by modulating leptin responsiveness. Specifically, we identified a subset of microRNA (miRNA) within Ad-EVs that exerts leptin-sensitizing effects by inhibiting negative feedback regulators of leptin receptor signaling. Loss of these leptin-sensitizing miRNAs in Ad-EVs contributes to leptin resistance and subsequent weight gain in obesity. Of note, we developed engineered EVs modified with specific Ad-EV membrane proteins for targeted delivery of leptin-sensitizing miRNAs to the central nervous system, which reversed central leptin resistance and induced significant weight loss in obese mice. These findings highlight the critical role of Ad-EVs in central leptin sensitivity regulation, offering new insights into the role of the adipose tissue-brain axis in maintaining energy balance and potential pharmacological targets for obesity treatment.
    Keywords:  adipose tissue; energy homeostasis; extracellular vesicles; leptin resistance; microRNA; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.10.005
  6. JCI Insight. 2025 Nov 11. pii: e189683. [Epub ahead of print]
    Mutation in IR or IGF1R produces features of long-lived mice while maintaining metabolic health.
    Ulalume Hernández-Arciga, Jun Kyoung Kim, Jacob L Fisher, Alexander Tyshkovskiy, Alibek Moldakozhayev, Catherine Hall, Souvik Ghosh, Yashvandhini Govindaraj, Ian J Sipula, Jake Kastroll, Diana Cooke, Jinping Luo, Jonathan K Alder, Stacey J Sukoff Rizzo, Gene P Ables, Eunhee Choi, Vadim N Gladyshev, Michael J Jurczak, Marc Tatar, Andrey A Parkhitko.
      Insulin/insulin growth factor signaling is a conserved pathway that regulates lifespan. Yet, long-lived loss-of-function mutants often produce insulin-resistance, slow growth, and impair reproduction. Recently, a gain-of-function mutation in the kinase insert domain (KID) of the Drosophila insulin/IGF receptor was seen to dominantly extend lifespan without impairing insulin-sensitivity, growth and reproduction. This substitution occurs within residues conserved in mammalian insulin receptor (IR) and insulin growth factor-1 receptor (IGF-1R). We produced two knock-in mouse strains that carry the homologous KID Arg/Cys substitution in murine IR or IGF-1R, and we replicated these genotypes in human cells. Cells with heterodimer receptors of IR or IGF-1R induce receptor phosphorylation and phospho-Akt when stimulated with insulin or IGF. Heterodimer receptors of IR fully induce pERK but ERK was less phosphorylated in cells with IGF-1R heterodimers. Adults with a single KID allele (producing heterodimer receptors) have normal growth and glucose regulation. At four months, these mice variably display hormonal markers that associate with successful aging counteraction, including elevated adiponectin, FGF21, and reduced leptin and IGF-1. Livers of IGF-1R females show decreased transcriptome-based biological age, which may point toward delayed aging and warrants an actual lifespan experiment. These data suggest that KID mutants may slow mammalian aging while they avoid the complications of insulin resistance.
    Keywords:  Aging; Glucose metabolism; Insulin; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.189683
  7. Cell Mol Life Sci. 2025 Nov 13. 82(1): 393
    Hepatocyte Piezo1 regulates glycogen metabolism via the FGF21-STAT3 pathway.
    Tian Tao, Ke Yang, Zhenming Li, Mengyuan Zhang, Zhejiao Zhang, Jinghui Guo, Hui Chen, Geyang Xu.
      The metabolism of glycogen in the liver plays a crucial role in regulating blood glucose levels. Previous studies have underscored the critical involvement of Piezo1 in glucose metabolism. However, the role of Piezo1 in hepatic glycogen metabolism remain unexplored. We induced liver-specific deletion of Piezo1 in Piezo1fl/fl mice using Cre adenovirus via tail vein injection. Compared to Piezo1fl/fl treated with GFP adenovirus, those treated with AAV-Cre exhibited impaired glucose tolerance, elevated GYS2 and PYGL levels, and decreased FGF21 levels, implicating inhibition of the STAT3 signaling pathway. Furthermore, mice with hepatocyte-specific Piezo1 deletion (Alb-Piezo1-/-) on a high-fat diet experienced exacerbated blood glucose levels, decreased hepatic FGF21 production, and enhanced PYGL expression and activity. These effects were alleviated by PF-05231023, an FGF21 analog. Additionally, intraperitoneal injection of Yoda1, a Piezo1 agonist, raised FGF21 levels, activating the STAT3 pathway and suppressing PYGL activity, thereby improving glucose tolerance. In vitro studies showed that knockdown of Piezo1 or Stat3 increased PYGL expression. Conversely, activation of Piezo1 led to decreased PYGL expression. Our study reveals a previously unexplored regulatory mechanism of glycogen metabolism by Piezo1 in liver cells, offering new insights into diabetes treatment.
    Keywords:  GYS2; Hepatic glycogen metabolism; PYGL; Piezo1
    DOI:  https://doi.org/10.1007/s00018-025-05921-4
  8. Nature. 2025 Nov 12.
    Estimation and mapping of the missing heritability of human phenotypes.
    Pierrick Wainschtein, Yuanxiang Zhang, Jeremy Schwartzentruber, Irfahan Kassam, Julia Sidorenko, Petko P Fiziev, Huanwei Wang, Jeremy McRae, Richard Border, Noah Zaitlen, Sriram Sankararaman, Michael E Goddard, Jian Zeng, Peter M Visscher, Kyle Kai-How Farh, Loic Yengo.
      Rare coding variants shape inter-individual differences in human phenotypes1. However, the contribution of rare non-coding variants to those differences remains poorly characterized. Here we analyse whole-genome sequence (WGS) data from 347,630 individuals with European ancestry in the UK Biobank2,3 to quantify the relative contribution of 40 million single-nucleotide and short indel variants (with a minor allele frequency (MAF) larger than 0.01%) to the heritability of 34 complex traits and diseases. On average across phenotypes, we find that WGS captures approximately 88% of the pedigree-based narrow sense heritability: that is, 20% from rare variants (MAF < 1%) and 68% from common variants (MAF ≥ 1%). We show that coding and non-coding genetic variants account for 21% and 79% of the rare-variant WGS-based heritability, respectively. We identified 15 traits with no significant difference between WGS-based and pedigree-based heritability estimates, suggesting their heritability is fully accounted for by WGS data. Finally, we performed genome-wide association analyses of all 34 phenotypes and, overall, identified 11,243 common-variant associations and 886 rare-variant associations. Altogether, our study provides high-precision estimates of rare-variant heritability, explains the heritability of many phenotypes and demonstrates for lipid traits that more than 25% of rare-variant heritability can be mapped to specific loci using fewer than 500,000 fully sequenced genomes.
    DOI:  https://doi.org/10.1038/s41586-025-09720-6
  9. Cell Rep Med. 2025 Nov 06. pii: S2666-3791(25)00499-9. [Epub ahead of print] 102426
    Glucocorticoid-induced changes of the gut microbiota and metabolic markers in healthy young men: Outcome of a randomized controlled trial.
    Liwei Lyu, Yong Fan, Thomas Bryrup, Marc Clos-Garcia, Susanne Brix, Markus Eiken, Evelina Stankevic, Asger Bach Lund, Filip Krag Knop, Niklas Rye Jørgensen, Henrik Vestergaard, Torben Hansen, Tue Hansen, Trine Nielsen, Oluf Pedersen.
      Glucocorticoids induce insulin resistance and suppress immunity, but their impact on gut microbiota, which may modulate metabolism and immunity remains under explored. In this 7-day trial, we assess glucocorticoid-induced changes in gut microbiota and metabolic markers in 56 healthy men, randomly assigned to three interventions: oral prednisolone (PO group), intramuscular methylprednisolone acetate (IM group), or saline (CTL group). Shotgun metagenomics reveal that PO glucocorticoid causes shifts in bacterial abundance, increasing Blautia and Collinsella, while decreasing Dysosmobacter welbionis and Anaerotignum faecicola, linked with insulin resistance and immunosuppression markers. Additionally, PO treatment alters microbial pathways and enzymes related to glycolysis and lipid metabolism, with changes in predicted metabolites such as hypoxanthine and phenylacetate. IM treatment results in minimal microbiota changes. These findings underscore the route-dependent effects of glucocorticoids on gut microbiota and their potential impact on host metabolism and immunity. The trial was approved by the Danish Medicine Agency (EudraCT protocol number: 2016-001850-16).
    Keywords:  glucocorticoids; gut microbiota; intervention trial; intramuscular injection; metabolic markers; microbial metabolites; per oral; randomized controlled trial
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102426
  10. Science. 2025 Nov 13. eadw5137
    Termination of the integrated stress response.
    Claudia De Miguel, Sigurdur R Thorkelsson, Agnieszka Fatalska, George Hodgson, Chao Wang, Anne Bertolotti.
      Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.
    DOI:  https://doi.org/10.1126/science.adw5137
  11. J Clin Invest. 2025 Nov 11. pii: e198387. [Epub ahead of print]
    Lamin A/C regulates lipid metabolism and inflammation: insights from models of familial partial lipodystrophy 2.
    Jessica N Maung, Rebecca L Schill, Akira Nishii, Maria Foss de Freitas, Bonje N Obua, Marcus Nygård, Maria D Mendez-Casillas, Isabel Dk Hermsmeyer, Donatella Gilio, Ozge Besci, Yang Chen, Brian Desrosiers, Rose E Adler, Anabela D Gomes, Merve Celik Guler, Hiroyuki Mori, Romina M Uranga, Ziru Li, Hadla Hariri, Liping Zhang, Anderson de Paula Souza, Keegan S Hoose, Kenneth T Lewis, Taryn A Hetrick, Paul Cederna, Carey N Lumeng, Susanne Mandrup, Elif A Oral, Ormond A MacDougald.
      Familial partial lipodystrophy 2 (FPLD2) is a rare disease characterized by adipose tissue loss and redistribution, and metabolic dysfunction. FPLD2 is caused by pathogenic variants in the LMNA gene, encoding nuclear lamins A/C, structural proteins that control nuclear function and gene expression. However, the mechanisms driving adipocyte loss in FPLD2 remain poorly defined. In this study, we recruited eight families with developing or established FPLD2 and performed clinical, histological, and transcriptomic analyses of subcutaneous adipose tissue biopsies. Bulk and single-nuclei RNA-sequencing revealed suppression of lipid metabolism and mitochondrial pathways, alongside increased inflammation. These signatures were mirrored in tamoxifen-inducible adipocyte-specific Lmna knockout mice, in which lamin A/C-deficient adipocytes shrank and disappeared. Lmna-deficient fibroblasts shared similar gene expression changes, linked to altered chromatin accessibility, underscoring lamin A/C's potential regulatory role in lipid metabolism and inflammatory programs. By directly comparing atrophic and hypertrophic adipose depots in FPLD2, and integrating human, mouse, and in vitro models, this study provides new insights into disease progression and potential therapeutic targets.
    Keywords:  Adipose tissue; Bioinformatics; Clinical Research; Genetic diseases; Metabolism
    DOI:  https://doi.org/10.1172/JCI198387
  12. Nature. 2025 Nov 12.
    iPEX enables micrometre-resolution deep spatial proteomics via tissue expansion.
    Fengxiang Wang, Cuiji Sun, Tianshu William Wu, Yuting Fu, Yujing Fan, Shuchang Zhao, Kaiyin Huang, Zijian Pan, Yang Lu, Jingrong Regina Han, Shikai Jia, Lizhou Zeng, Sheng Zhang, Ting Chen, Shaowei An, Shuang Susie Meng, Xun Guo, Weizhe Li, Heyuan Lian, Xiaoting Sun, Jin Hu, Chuanzhen Yang, Shan Feng, Pengfei Li, Liyuan Du, Xiaodong Liu, Kiryl D Piatkevich, Yilong Zou.
      The number of spatial omics technologies being developed is increasing1. However, a missing tool is one that can locate proteins in tissues in an untargeted manner at high spatial resolution and coverage. Here we present in situ imaging proteomics via expansion (iPEX), which integrates isotropic tissue magnification2 with matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging. iPEX provides scalable spatial resolution down to the micrometre scale and substantially increases the sensitivity of protein identification by 10-100-fold. Using the retina as a model, iPEX enabled the construction of spatial proteomic maps with high precision, the visualization of single-cell layers and extrasomatic structures and the identification of colocalized proteins. iPEX was readily applied to diverse tissues, including brain, intestine, liver and organoids, detecting 600-1,500 proteins at 1-5-µm effective pixel size. The application of iPEX to depict spatial proteomic maps in brains of mice with 5xFAD Alzheimer's disease revealed an early-onset mitochondrial aberrancy. Notably, in young mice, the peroxisomal acetyl-CoA acyltransferase ACAA1A-of which the N392S mutant is a monogenic risk factor in Alzheimer's disease3-was downregulated. ACAA1 depletion blocked the biosynthesis of long-chain polyunsaturated fatty acids, including docosahexaenoic acid, in multiple cellular contexts. These lipidome alterations were restored in cells overexpressing wild-type ACAA1 but not ACAA1(N392S), which suggests that the dysregulation of long-chain polyunsaturated fatty acids has an early role in neurodegeneration. Together, these results demonstrate that iPEX facilitates untargeted spatial proteomics at micrometre resolution for diverse applications.
    DOI:  https://doi.org/10.1038/s41586-025-09734-0
  13. Nat Cell Biol. 2025 Nov 11.
    Reprogramming of H3K36me2 guides lineage-specific post-implantation de novo DNA methylation.
    Xukun Lu, Lijuan Wang, Bofeng Liu, Xiaoyu Hu, Zhengmao Wang, Ling Liu, Guang Yu, Lijun Dong, Feng Kong, Qiang Fan, Yu Zhang, Wei Xie.
      In mammals, DNA methylation is re-established after implantation following post-fertilization global erasure. Yet, the underlying mechanism remains elusive. Here we investigate H3K36me2 reprogramming in mouse early development and its role in post-implantation DNA methylation re-establishment. In oocytes, H3K36me2 accumulates in gene bodies upon transcription silencing and partially persists to the eight-cell stage. De novo H3K36me2 occurs at enhancers after zygotic genome activation, before spreading genome-wide after implantation, except on the inactive X chromosome. Mutation of the H3K36me2 methyltransferase NSD1 compromises global DNA methylation after implantation preferentially in extra-embryonic lineages and that at methylation-prone promoters, including those of germline-specific genes. However, DNA methylation establishment partially bypasses H3K36me2 through upregulated DNMT3B, a 'leaky' H3K36me2/3 reader. This contrasts with DNMT3A, which strictly requires H3K36me2/3 for DNA methylation through its PWWP domain. Finally, DNA methylation valleys escape de novo DNA methylation via PRC1/H2AK119ub1-mediated H3K36me2 exclusion. Thus, H3K36me2 reprogramming regulates lineage- and locus-specific post-implantation DNA methylation establishment.
    DOI:  https://doi.org/10.1038/s41556-025-01805-8
  14. Adv Sci (Weinh). 2025 Nov 14. e12657
    Targeting Endothelial KDM5A to Attenuate Aging and Ameliorate Age-Associated Metabolic Abnormalities.
    Rifeng Gao, Lifeng Liang, Ling Yang, Chunyu Lyu, Yang Lyu, Weijun Yang, Jiaran Shi, Wei Wei, Jiahui Cheng, Xiaolei Sun, Xian Zhu, Chao Chen, Xiaoting Xu, Jianchuang Qi, Wenli Li, Yizhe Zhang, Xiao Zhang, Yan Zhou, Aiqiang Dong, Juntao Chen, Bo Li, Kun Yang.
      Vascular aging accelerates the gradual deterioration of systemic organ function, yet its key driving factors are still largely unexplored. Here, it is demonstrated that lysine-specific demethylase 5A (KDM5A) decreases and histone H3 lysine 4 (H3K4me3) increases in vascular endothelial cells (VECs) isolated from ageing mice and VEC senescence models. KDM5A deficiency exacerbated endothelial cell aging in vitro. Endothelial-specific KDM5A-deficient mice exhibit shortened lifespan and multiple senescent phenotypes, including fat accumulation, reduced thermogenic capacity, skeletal kyphosis, and age-related liver lesions, while maintaining VECs-specific KDM5A levels attenuates these adverse metabolic abnormalities and prolongs lifespan. Mechanistically, endothelial KDM5A deficiency aggravates aging-associated fatty acid (FA) metabolism disorders by enhancing H3K4me3 enrichment at the promoter region of FA-binding protein 4 (FABP4), which leads to active FABP4 transcription. Together, the study reveals the regulatory mechanisms of KDM5A in age-dependent metabolic disorders and identifies KDM5A/FABP4 axis as a potential therapeutic target for vascular aging and related organ dysfunction.
    Keywords:  FABP4; KDM5A; aging; metabolic abnormalities; vascular endothelial cells
    DOI:  https://doi.org/10.1002/advs.202512657
  15. Nat Genet. 2025 Nov;57(11): 2620
    Somatic mutations at scale.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02438-1
  16. Mol Cell. 2025 Nov 07. pii: S1097-2765(25)00854-8. [Epub ahead of print]
    Alternative start codon selection shapes mitochondrial function and rare human diseases.
    Jimmy Ly, Matteo Di Bernardo, Yi Fei Tao, Ekaterina Khalizeva, Christopher J Giuliano, Sebastian Lourido, Mark D Fleming, Iain M Cheeseman.
      Rare genetic diseases collectively affect millions of individuals. A common target of many rare diseases is the mitochondria, intracellular organelles that originated through endosymbiosis. Eukaryotic cells require related proteins to function both within the mitochondria and in the host cell. By analyzing N-terminal protein isoforms generated through alternative start codon selection, we identify hundreds of differentially localized isoform pairs, including dual-localized isoforms that are essential for both mitochondrial and host cell function. Subsets of dual mitochondria-localized isoforms emerged during early eukaryotic evolution, coinciding with mitochondrial endosymbiosis. Importantly, we identify dozens of rare disease alleles that affect these alternative protein variants with unique molecular and clinical consequences. Alternative start codon selection can bypass pathogenic nonsense and frameshift mutations, thereby selectively eliminating specific isoforms, which we term isoform-selective alleles (ISAs). Together, our findings illuminate the evolutionary and pathological relevance of alternative translation, offering insights into the molecular basis of rare human diseases.
    Keywords:  TRNT1; alternative N-terminal isoforms; alternative translation; mitochondria; proteomic diversity; rare diseases; start codon selection; translation initiation
    DOI:  https://doi.org/10.1016/j.molcel.2025.10.013
  17. Am J Hum Genet. 2025 Nov 12. pii: S0002-9297(25)00403-3. [Epub ahead of print]
    A deep dive into statistical modeling of RNA splicing QTLs reveals variants that explain neurodegenerative disease.
    David Wang, Matthew R Gazzara, San Jewell, Benjamin D Wales-McGrath, Kevin Yang, Christopher D Brown, Peter S Choi, Yoseph Barash.
      Genome-wide association studies (GWASs) have identified thousands of putative disease-causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show that current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a pipeline for sQTL discovery. MAJIQTL includes two statistical methods: a weighted multiple-testing approach for sGene discovery and a model for sQTL effect-size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the variant rs528823 in Alzheimer disease. Using antisense oligonucleotides, we test this variant's effect by blocking the implicated YBX3 binding site, leading to exon skipping in MS4A3.
    Keywords:  Alzheimer; MAJIQ; MS4A3; Parkinson; RNA splicing; RNA-seq; effect size; sQTL; statistical genetics; weighted hypothesis testing
    DOI:  https://doi.org/10.1016/j.ajhg.2025.10.012
  18. Cell. 2025 Nov 13. pii: S0092-8674(25)01150-X. [Epub ahead of print]188(23): 6391-6392
    Unlocking rejuvenating potential of mesenchymal progenitor cells.
    Vera Gorbunova, Andrei Seluanov.
      Age-dependent exhaustion of endogenous stem cell pools-and the resulting decline in tissue regeneration and homeostatic maintenance-is a hallmark of organismal aging and age-related pathology. In a study published in Cell, Liu and collaborators engineered human ESC-derived mesenchymal progenitor cells to give the ability to resist senescence, environmental stress, and malignant transformation.
    DOI:  https://doi.org/10.1016/j.cell.2025.10.011
  19. Nature. 2025 Nov 12.
    Cytosolic acetyl-coenzyme A is a signalling metabolite to control mitophagy.
    Yifan Zhang, Xiao Shen, Yuan Shen, Chao Wang, Chengping Yu, Jiangxue Han, Siyi Cao, Lin Qian, Miaolian Ma, Shijing Huang, Wenyu Wen, Miao Yin, Qun-Ying Lei.
      Acetyl-coenzyme A (AcCoA) sits at the nexus of nutrient metabolism and shuttles between the canonical and non-canonical tricarboxylic acid cycle1,2, which is dynamically regulated by nutritional status, such as fasting3. Here we find that mitophagy is triggered after a reduction in cytosolic AcCoA levels through short-term fasting and through inhibition of ATP-citrate lyase (encoded by ACLY), mitochondrial citrate/malate antiporter (encoded by SLC25A1) or acyl-CoA synthetase short chain family member 2 (encoded by ACSS2), and the mitophagy can be counteracted by acetate supplementation. Notably, NOD-like receptor (NLR) family member X1 (NLRX1) mediates this effect. Disrupting NLRX1 abolishes cytosolic AcCoA reduction-induced mitophagy both in vitro and in vivo. Mechanically, the mitochondria outer-membrane-localized NLRX1 directly binds to cytosolic AcCoA within a conserved pocket on its leucine-rich repeat (LRR) domain. Moreover, AcCoA binds to the LRR domain and enhances its interaction with the nucleotide-binding and oligomerization (NACHT) domain, which helps to maintain NLRX1 in an autoinhibited state and prevents the association between NLRX1 and light chain 3 (LC3). Furthermore, we find that the AcCoA-NLRX1 axis underlies the KRAS-inhibitor-induced mitophagy response and promotes drug resistance, providing a metabolic mechanism of KRAS inhibitor resistance. Thus, cytosolic AcCoA is a signalling metabolite that connects metabolism to mitophagy through its receptor NLRX1.
    DOI:  https://doi.org/10.1038/s41586-025-09745-x
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