bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–05–18
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.
  2. YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ.
  3. Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
  4. The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.
  5. Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress.
  6. Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity.
  7. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
  8. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
  9. FGF21 reverses MASH through coordinated actions on the CNS and liver.
  10. Depletion of WWP1 Increases Adrb3 Expression and Lipolysis in White Adipose Tissue of Obese Mice.
  11. Incidence, prevalence, and burden of type 2 diabetes in China: Trend and projection from 1990 to 2050.
  12. Adipocyte metabolic state regulates glial phagocytic function.
  13. Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7.
  14. Cell type- and factor-specific nonsense-mediated RNA decay.
  1. Nat Commun. 2025 May 13. 16(1): 4432
    Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.
    Nagasuryaprasad Kotikalapudi, Deepti Ramachandran, Daniel Vieira, William B Rubio, Gregory R Gipson, Luca Troncone, Kylie Vestal, David E Maridas, Vicki Rosen, Paul B Yu, Thomas B Thompson, Alexander S Banks.
      TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here we describe a role for Growth Differentiation Factor 3 (GDF3) on mature adipocyte biology. We find inducible GDF3 loss of function in obese adult mice leads to reduced lipolysis, improved glucose tolerance, and reduced glycemic variability. The effects on lipolysis are driven by lower levels of β3-adrenergic receptor, decreased cAMP and PKA signaling. GDF3 is an ALK5, ALK7, ACVR2A and ACVR2B agonist and also a BMPR2 antagonist. Unlike ALK7 or activin E knockouts, acute GDF3 loss of function does not affect body weight or energy balance but significantly improves metabolic health. These results suggest that blocking GDF3 can improve metabolic health independent of body weight and food intake, an intriguing new model for developing anti-diabetic therapies. Together these results provide much-needed clarity to both the molecular pathways involved in GDF3 signaling and its physiological effects.
    DOI:  https://doi.org/10.1038/s41467-025-59673-7
  2. EMBO J. 2025 May 12.
    YTHDC1 promotes postnatal brown adipose tissue development and thermogenesis by stabilizing PPARγ.
    Lihua Wang, Yuqin Wang, Kaixin Ding, Zhenzhi Li, Zhipeng Zhang, Xinzhi Li, Yue Song, Liwei Xie, Zheng Chen.
      Brown adipose tissue (BAT) plays a vital role in non-shivering thermogenesis and energy metabolism and is influenced by factors like environmental temperature, ageing, and obesity. However, the molecular mechanisms behind BAT development and thermogenesis are not fully understood. Our study identifies the m6A reader protein YTHDC1 as a crucial regulator of postnatal interscapular BAT development and energy metabolism in mice. YTHDC1 directly interacts with PPARγ through its intrinsically disordered region (IDR), thus protecting PPARγ from binding the E3 ubiquitin ligase ARIH2, and preventing its ubiquitin-mediated proteasomal degradation. Specifically, the ARIH2 RING2 domain is essential for PPARγ degradation, while PPARγ's A/B domain is necessary for their interaction. Deletion of Ythdc1 in BAT increases PPARγ degradation, impairing interscapular BAT development, thermogenesis, and overall energy expenditure. These findings reveal a novel mechanism by which YTHDC1 regulates BAT development and energy homeostasis independently of its m6A recognition function.
    Keywords:  Brown Adipose Tissue; Intrinsically Disordered Region; PPARγ; Thermogenesis; YTHDC1
    DOI:  https://doi.org/10.1038/s44318-025-00460-x
  3. Nat Metab. 2025 May 13.
    Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
    Anne Loft, Margo P Emont, Ada Weinstock, Adeline Divoux, Adhideb Ghosh, Allon Wagner, Ann V Hertzel, Babukrishna Maniyadath, Bart Deplancke, Boxiang Liu, Camilla Scheele, Carey Lumeng, Changhai Ding, Chenkai Ma, Christian Wolfrum, Clarissa Strieder-Barboza, Congru Li, Danh D Truong, David A Bernlohr, Elisabet Stener-Victorin, Erin E Kershaw, Esti Yeger-Lotem, Farnaz Shamsi, Hannah X Hui, Henrique Camara, Jiawei Zhong, Joanna Kalucka, Joseph A Ludwig, Julie A Semon, Jutta Jalkanen, Katie L Whytock, Kyle D Dumont, Lauren M Sparks, Lindsey A Muir, Lingzhao Fang, Lucas Massier, Luis R Saraiva, Marc D Beyer, Marc G Jeschke, Marcelo A Mori, Mariana Boroni, Martin J Walsh, Mary-Elizabeth Patti, Matthew D Lynes, Matthias Blüher, Mikael Rydén, Natnael Hamda, Nicole L Solimini, Niklas Mejhert, Peng Gao, Rana K Gupta, Rinki Murphy, Saeed Pirouzpanah, Silvia Corvera, Su'an Tang, Swapan K Das, Søren F Schmidt, Tao Zhang, Theodore M Nelson, Timothy E O'Sullivan, Vissarion Efthymiou, Wenjing Wang, Yihan Tong, Yu-Hua Tseng, Susanne Mandrup, Evan D Rosen.
      Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.
    DOI:  https://doi.org/10.1038/s42255-025-01296-9
  4. EMBO J. 2025 May 12.
    The microprotein C16orf74/MICT1 promotes thermogenesis in brown adipose tissue.
    Jennie Dinh, Danielle Yi, Frances Lin, Pengya Xue, Nicholas D Holloway, Ying Xie, Nnejiuwa U Ibe, Hai P Nguyen, Jose A Viscarra, Yuhui Wang, Hei Sook Sul.
      Brown and beige adipose tissues are metabolically beneficial for increasing energy expenditure via thermogenesis, mainly through UCP1 (uncoupling protein 1). Here, we identify C16orf74, subsequently named MICT1 (microprotein for thermogenesis 1), as a microprotein that is specifically and highly expressed in brown adipose tissue (BAT) and is induced upon cold exposure. MICT1 interacts with protein phosphatase 2B (PP2B, calcineurin) through the docking motif PNIIIT, thereby interfering with dephosphorylation of the regulatory subunit of protein kinase A (PKA), RIIβ, and potentiating PKA activity in brown adipocytes. Overexpression of MICT1 in differentiated brown adipocytes promotes thermogenesis, showing increased oxygen consumption rate (OCR) with higher thermogenic gene expression during β3-adrenergic stimulation, while knockdown of MICT1 impairs thermogenic responses. Moreover, BAT-specific MICT1 ablation in mice suppresses thermogenic capacity to increase adiposity and insulin resistance. Conversely, MICT1 overexpression in BAT or treating mice with a chemical inhibitor that targets the PP2B docking motif of MICT1 enhances thermogenesis. This results in cold tolerance and increased energy expenditure, protection against diet-induced and genetic obesity and insulin resistance, thus suggesting a therapeutic potential of MICT1 targeting.
    Keywords:  Brown Adipose Tissue (Thermogenesis); C16orf74 (MICT1); Microprotein; PP2B (Calcineurin); Protein Kinase A (PKA)
    DOI:  https://doi.org/10.1038/s44318-025-00444-x
  5. Nat Commun. 2025 May 14. 16(1): 4455
    Chaperone-mediated autophagy manipulates PGC1α stability and governs energy metabolism under thermal stress.
    Yixiao Zhuang, Xinyi Zhang, Shuang Zhang, Yunpeng Sun, Hui Wang, Yuxuan Chen, Hanyin Zhang, Penglai Zou, Yonghao Feng, Xiaodan Lu, Peijie Chen, Yi Xu, John Zhong Li, Huanqing Gao, Li Jin, Xingxing Kong.
      Thermogenic proteins are down-regulated under thermal stress, including PGC1α· However, the molecular mechanisms are not fully understood. Here, we addressed that chaperone-mediated autophagy could regulate the stability of PGC1α under thermal stress. In mice, knockdown of Lamp2a, one of the two components of CMA, in BAT showed increased PGC1α protein and improved metabolic phenotypes. Combining the proteomics of brown adipose tissue (BAT), structure prediction, co-immunoprecipitation- mass spectrum and biochemical assays, we found that PARK7, a Parkinson's disease causative protein, could sense the temperature changes and interact with LAMP2A and HSC70, respectively, subsequently manipulate the activity of CMA. Knockout of Park7 specific in BAT promoted BAT whitening, leading to impaired insulin sensitivity and energy expenditure at thermoneutrality. Moreover, inhibiting the activity of CMA by knockdown of LAMP2A reversed the effects induced by Park7 ablation. These findings suggest CMA is required for BAT to sustain thermoneutrality-induced whitening through degradation of PGC1α.
    DOI:  https://doi.org/10.1038/s41467-025-59618-0
  6. Nat Commun. 2025 May 12. 16(1): 4374
    Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity.
    Aino Heikkinen, Vivienne F C Esser, Seung Hyuk T Lee, Sara Lundgren, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Sini Heinonen, Sergio Villicaña, Jordana T Bell, Alice Maguolo, Emma Nilsson, Charlotte Ling, Allan Vaag, Päivi Pajukanta, Jaakko Kaprio, Kirsi H Pietiläinen, Shuai Li, Miina Ollikainen.
      Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.
    DOI:  https://doi.org/10.1038/s41467-025-59576-7
  7. Nat Aging. 2025 May 12.
    Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging.
    Seyed Soheil Saeedi Saravi, Benoit Pugin, Florentin Constancias, Khatereh Shabanian, Marianne Spalinger, Aurélien Thomas, Sylvain Le Gludic, Taraneh Shabanian, Gergely Karsai, Manuel Colucci, Cristina Menni, Ilias Attaye, Xinyuan Zhang, Meret Sarah Allemann, Pratintip Lee, Alessia Visconti, Mario Falchi, Andrea Alimonti, Frank Ruschitzka, Francesco Paneni, Jürg H Beer.
      Endothelial cell senescence is a key driver of cardiovascular aging, yet little is known about the mechanisms by which it is induced in vivo. Here we show that the gut bacterial metabolite phenylacetic acid (PAA) and its byproduct, phenylacetylglutamine (PAGln), are elevated in aged humans and mice. Metagenomic analyses reveal an age-related increase in PAA-producing microbial pathways, positively linked to the bacterium Clostridium sp. ASF356 (Clos). We demonstrate that colonization of young mice with Clos increases blood PAA levels and induces endothelial senescence and angiogenic incompetence. Mechanistically, we find that PAA triggers senescence through mitochondrial H2O2 production, exacerbating the senescence-associated secretory phenotype. By contrast, we demonstrate that fecal acetate levels are reduced with age, compromising its function as a Sirt1-dependent senomorphic, regulating proinflammatory secretion and redox homeostasis. These findings define PAA as a mediator of gut-vascular crosstalk in aging and identify sodium acetate as a potential microbiome-based senotherapy to promote healthy aging.
    DOI:  https://doi.org/10.1038/s43587-025-00864-8
  8. Cell Metab. 2025 May 08. pii: S1550-4131(25)00253-0. [Epub ahead of print]
    Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
    Jessica W Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Monther Abu-Remaileh, Judith A Simcox.
      Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
    Keywords:  BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.015
  9. Cell Metab. 2025 May 08. pii: S1550-4131(25)00252-9. [Epub ahead of print]
    FGF21 reverses MASH through coordinated actions on the CNS and liver.
    Jesse P Rose, Donald A Morgan, Andrew I Sullivan, Xiaorong Fu, Melissa Inigo-Vollmer, Shawn C Burgess, David K Meyerholz, Kamal Rahmouni, Matthew J Potthoff.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), represent a growing public health burden with limited therapeutic options. Recent studies have revealed that fibroblast growth factor 21 (FGF21)-based analogs can significantly improve MASH, but the mechanisms for this effect are not well understood. Here, we demonstrate that the beneficial metabolic effects of FGF21 to reverse MASH are mediated through distinct mechanisms to independently lower hepatic triglyceride and cholesterol levels. Specifically, FGF21 signaling directly to glutamatergic neurons in the central nervous system (CNS) stimulates hepatic triglyceride reduction and reversal of fibrosis, whereas FGF21 signaling directly to hepatocytes is necessary and sufficient to reduce hepatic cholesterol levels in mice. Mechanistically, we show that FGF21 acts in the CNS to increase sympathetic nerve activity to the liver, which suppresses hepatic de novo lipogenesis. These results provide critical insights into a promising pharmacological target to treat MASH.
    Keywords:  FGF21; MASH; MASLD; betaklotho; brain; hepatic innervation; hepatokine; liver; sympathetic nerve activity
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.014
  10. Int J Mol Sci. 2025 Apr 29. pii: 4219. [Epub ahead of print]26(9):
    Depletion of WWP1 Increases Adrb3 Expression and Lipolysis in White Adipose Tissue of Obese Mice.
    Yuka Nozaki, Yuko Ose, Chinatsu Ohmori, Yuhei Mizunoe, Masaki Kobayashi, Akiyoshi Saitoh, Yoshikazu Higami.
      Obesity is defined as abnormal or excessive accumulation of body fat and contributes to several metabolic disorders. White adipose tissue (WAT) releases energy as free fatty acids and glycerol from triglycerides through a process called lipolysis. People with obesity have impaired catecholamine-stimulated lipolysis, but comprehensive understanding of this lipolysis is still unclear. We previously showed that expression of WW domain-containing E3 ubiquitin ligase 1 (WWP1), a member of the HECT-type E3 family of ubiquitin ligases, was increased in WAT of obese mice. In this study, we generated Wwp1 knockout (KO) mice to evaluate the effect of WWP1 in WAT of obese mice. The mRNA levels of beta-3 adrenergic receptor (Adrb3), which were decreased with a high-fat diet, were increased by Wwp1 KO in WAT. Moreover, Wwp1 KO mice showed increased phosphorylated hormone-sensitive lipase levels in WAT. In contrast, noradrenaline and its metabolism were not altered in WAT of obese Wwp1 KO mice. These findings indicate that WWP1, which is increased in adipocytes because of obesity, is a candidate for suppressing lipolysis independently of noradrenaline metabolism. We anticipate that inhibition of WWP1 is a promising approach for a new treatment of obesity and type-2 diabetes using Adrb3 agonists.
    Keywords:  Adrb3; WWP1; lipolysis; white adipose tissue
    DOI:  https://doi.org/10.3390/ijms26094219
  11. Chin Med J (Engl). 2025 May 16.
    Incidence, prevalence, and burden of type 2 diabetes in China: Trend and projection from 1990 to 2050.
    Haojie Zhang, Qingyi Jia, Peige Song, Yongze Li, Lihua Jiang, Xianghui Fu, Sheyu Li.
       BACKGROUND: Type 2 diabetes is common in China without comprehensive summary and future anticipation of its incidence, prevalence, associated death, and disability. This analysis described the epidemiological transition of type 2 diabetes in the past three decades and projected the trend in the future three decades in China.
    METHODS: Age-, sex-, and year-specific incidence, prevalence, death, and disability-adjusted life years (DALYs) for people with 15 years or older and diabetes or high fasting glucose in China and related countries from 1990 to 2021 were obtained from the Global Burden of Disease. We obtained the trends of age-, sex-, and year-specific rates and absolute numbers of incidence, prevalence, deaths, and DALYs attributable to type 2 diabetes in China from 1990 to 2021. Using the Lee-Carter model, we projected the incidence, prevalence, deaths, and DALYs attributable to type 2 diabetes to 2050 stratified by age and sex.
    RESULTS: The age-standardized incidence of type 2 diabetes was 341.5 per 100,000 persons (1.6 times in 1990) and the age-standardized prevalence was 9960.0 per 100,000 persons (2.5 times in 1990) in China 2021. In 2021, there were 0.9 million deaths and 26.8 million DALYs due to type 2 diabetes or hyperglycemia, as 2.9 and 2.7 times the data in 1990, respectively. In the projection, the age-standardized incidence (449.5 per 100,000 persons in 2050) will continue to increase but the growing rate will slow down in the future decades. With the population aging, there will be estimated 211.2 million Chinese people with type 2 diabetes with an anticipated age-standardized prevalence of 18,171.2 per 100,000 persons, 244.6 per 100,000 deaths, and 4720.2 per 100,000 DALYs in 2050. The incidence of type 2 diabetes kept growing among adolescents and young adults in the past three decades (128.7, 439.9, and estimated 1870.8 per 100,000 persons in 1990, 2021, and 2050, respectively).
    CONCLUSIONS: The incidence, prevalence, and disease burden of type 2 diabetes grew rapidly in China in the past three decades. The greatest challenges in the future three decades will be the prevention of type 2 diabetes in young people and the care for elder adults.
    Keywords:  Burden; Death; Disability-adjusted life years; Incidence; Prevalence; Projections; Type 2 diabetes
    DOI:  https://doi.org/10.1097/CM9.0000000000003536
  12. Cell Rep. 2025 May 14. pii: S2211-1247(25)00475-9. [Epub ahead of print]44(5): 115704
    Adipocyte metabolic state regulates glial phagocytic function.
    Mroj Alassaf, Aditi Madan, Sunidhi Ranganathan, Shannon Marschall, Jordan J Wong, Zachary H Goldberg, Ava E Brent, Akhila Rajan.
      Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions.
    Keywords:  ApoB; CP: Metabolism; CP: Neuroscience; Drosophila; OxPhos; adipokine; glycolysis; high-sugar diet; injury-response; ketogenesis; lipid metabolism; mitochondria; neurodegeneration; pyronic sensor
    DOI:  https://doi.org/10.1016/j.celrep.2025.115704
  13. Sci Adv. 2025 May 16. 11(20): eadu6632
    Dual DNA demethylation mechanisms implement epigenetic memory driven by the pioneer factor PAX7.
    Juliette Harris, Alexandre Mayran, Arthur Gouhier, Yves Gauthier, Nawal Hajj Sleiman, Samir Merabet, Michael Dukatz, Pavel Bashtrykov, Albert Jeltsch, Haig Djambazian, Shu-Huang Chen, Aurelio Balsalobre, Jacques Drouin.
      Pioneer transcription factors have the unique ability to open chromatin at enhancers to implement new cell fates. They also provide epigenetic memory through demethylation of enhancer DNA, but the underlying mechanisms remain unclear. We now show that the pioneer paired box 7 (PAX7) triggers DNA demethylation using two replication-dependent mechanisms, including direct PAX7 interaction with the E3 ubiquitin-protein ligase (UHRF1)-DNA methyltransferase 1 (DNMT1) complex that is responsible for DNA methylation maintenance. PAX7 binds to UHRF1 and prevents its interaction with DNMT1, thus blocking activation of its enzyme activity. The ten-eleven translocation DNA dioxygenase (TET) DNA demethylases also contribute to the replication-dependent loss of DNA methylation. Thus, PAX7 hijacks UHRF1 to block activation of DNMT1 after replication, leading to loss of DNA methylation by dilution, and the process is assisted by the action of TET demethylases.
    DOI:  https://doi.org/10.1126/sciadv.adu6632
  14. Nucleic Acids Res. 2025 May 10. pii: gkaf395. [Epub ahead of print]53(9):
    Cell type- and factor-specific nonsense-mediated RNA decay.
    Kun Tan, Jonathan Sebat, Miles F Wilkinson.
      Nonsense-mediated RNA decay (NMD) is a highly conserved RNA turnover pathway that influences several biological processes. Specific features in messenger RNAs (mRNAs) have been found to trigger decay by NMD, leading to the assumption that NMD sensitivity is an intrinsic quality of a given transcript. Here, we provide evidence that, instead, an overriding factor dictating NMD sensitivity is the cell environment. Using several genome-wide techniques to detect NMD-target mRNAs, we find that hundreds of mRNAs are sensitized to NMD as human embryonic stem cells progress to form neural progenitor cells. Another class of mRNAs escape from NMD during this developmental progression. We show that the differential sensitivity to NMD extends to in vivo scenarios, and that the RNA-binding protein, HNRNPL, has a role in cell type-specific NMD. We also addressed another issue in the field-whether NMD factors are core or branch-specific in their action. Surprisingly, we found that UPF3B, an NMD factor critical for the nervous system, shares only 30% of NMD-target transcripts with the core NMD factor UPF2. Together, our findings have implications for how NMD is defined and measured, how NMD acts in different biological contexts, and how different NMD branches influence human diseases.
    DOI:  https://doi.org/10.1093/nar/gkaf395
This page is being maintained by Thomas Krichel. It was last updated on 2025‒05‒18 at 15:27.