bims-obesme 2025-04-06 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–04–06
eighteen papers selected by
Xiong Weng, University of Edinburgh

Ceramide-induced FGF13 impairs systemic metabolic health.
Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.
Sex and Depot Specific Adipocyte Proteome Profiling In Vivo via Intracellular Proximity Labeling.
Exercise-induced anti-obesity effects in male mice generated by a FOXO1-KLF10 reinforcing loop promoting adipose lipolysis.
Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.
The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.
KIAA1199 (CEMIP) regulates adipogenesis and whole-body energy metabolism.
The FGF13-Caveolin-1 Axis: A Key Player in the Pathogenesis of Doxorubicin- and D-Galactose-Induced Premature Cardiac Aging.
Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics.
Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.
Crosstalk between metabolism and epigenetics during macrophage polarization.
O-GlcNAc transferase is a key regulator of DNA methylation and transposon silencing.
The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.
OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.
Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease.
Invigorating discovery and clinical translation of aging biomarkers.
Integration of GWAS, QTLs and keratinocyte functional assays reveals molecular mechanisms of atopic dermatitis.
PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms.

Cell Metab. 2025 Mar 26. pii: S1550-4131(25)00105-6. [Epub ahead of print]

Ceramide-induced FGF13 impairs systemic metabolic health.

Jamal Naderi, Amanda Kelsey Johnson, Himani Thakkar, Bhawna Chandravanshi, Alec Ksiazek, Ajay Anand, Vinnyfred Vincent, Aaron Tran, Anish Kalimireddy, Pratibha Singh, Ayushi Sood, Aasthika Das, Chad Lamar Talbot, Isabella A Distefano, J Alan Maschek, James Cox, Ying Li, Scott A Summers, Donald J Atkinson, Tursun Turapov, Jason A Ratcliff, Javis Fung, Asim Shabbir, M Shabeer Yassin, Sue-Anne Toh Ee Shiow, William L Holland, Geoffrey S Pitt, Bhagirath Chaurasia.

  Ceramide accumulation impairs adipocytes' ability to efficiently store and utilize nutrients, leading to energy and glucose homeostasis deterioration. Using a comparative transcriptomic screen, we identified the non-canonical, non-secreted fibroblast growth factor FGF13 as a ceramide-regulated factor that impairs adipocyte function. Obesity robustly induces FGF13 expression in adipose tissue in mice and humans and is positively associated with glycemic indices of type 2 diabetes. Pharmacological or genetic inhibition of ceramide biosynthesis reduces FGF13 expression. Using mice with loss and gain of function of FGF13, we demonstrate that FGF13 is both necessary and sufficient to impair energy and glucose homeostasis independent of ceramides. Mechanistically, FGF13 exerts these effects by inhibiting mitochondrial content and function, metabolic elasticity, and caveolae formation, which cumulatively impairs glucose utilization and thermogenesis. These studies suggest the therapeutic potential of targeting FGF13 to prevent and treat metabolic diseases.

Keywords:  FGF13; adipocytes; ceramides; diabetes; insulin resistance; lipotoxicity; obesity; sphingolipids

DOI:  https://doi.org/10.1016/j.cmet.2025.03.002
Nat Commun. 2025 Mar 28. 16(1): 3038

Targeting senescent hepatocytes for treatment of metabolic dysfunction-associated steatotic liver disease and multi-organ dysfunction.

Kuo Du, David S Umbaugh, Wang Liuyang, Ji Hye Jun, Rajesh K Dutta, Seh Hoon Oh, Niansheng Ren, Qiaojuan Zhang, Dennis C Ko, Ana Ferreira, Jon Hill, Guannan Gao, Steven S Pullen, Vaibhav Jain, Simon Gregory, Manal F Abdelmalek, Anna Mae Diehl.

Senescent hepatocytes accumulate in metabolic dysfunction-associated steatotic liver disease (MASLD) and are linked to worse clinical outcomes. However, their heterogeneity and lack of specific markers have made them difficult to target therapeutically. Here, we define a senescent hepatocyte gene signature (SHGS) using in vitro and in vivo models and show that it tracks with MASLD progression/regression across mouse models and large human cohorts. Single-nucleus RNA-sequencing and functional studies reveal that SHGS+ hepatocytes originate from p21+ cells, lose key liver functions and release factors that drive disease progression. One such factor, GDF15, increases in circulation alongside SHGS+ burden and disease progression. Through chemical screening, we identify senolytics that selectively eliminate SHGS+ hepatocytes and improve MASLD in male mice. Notably, SHGS enrichment also correlates with dysfunction in other organs. These findings establish SHGS+ hepatocytes as key drivers of MASLD and highlight a potential therapeutic strategy for targeting senescent cells in liver disease and beyond.

DOI: https://doi.org/10.1038/s41467-025-57616-w
Compr Physiol. 2025 Apr;15(2): e70007

Sex and Depot Specific Adipocyte Proteome Profiling In Vivo via Intracellular Proximity Labeling.

Taylor L Simonian, Amanda S Meyer, Jinjin Guo, Jihui Sha, James A Wohlschlegel, Ilia A Droujinine, Norbert Perrimon, Andrew P McMahon.

  Adipose tissue has varying distributions and metabolic properties between the sexes. Inherent sex-specific differences in adipocytes may heighten the risk of metabolic disease in males. Analysis of the adipocyte proteome can potentially provide important insight. To enable cell-type specific proteomic profiling in vivo, we genetically engineered a mouse line for cell-type specific production of a promiscuous biotin ligase (BirA*G3) facilitating the rapid isolation of biotinylated cell-type specific proteomes. Adipocyte-specific activation of cytoplasmic BirA*G3 led to robust biotinylation of adipocyte proteins across all major fat depots. Comparison of brown adipose tissue (BAT) and subcutaneous white adipose tissue (SAT) proteomes identified 229 brown adipose-enriched and 35 white adipose-enriched proteins. Regional comparison of white fat depots revealed additional differences across depots. Comparison of male and female depots identified sexually dimorphic adipose proteins: AHNAK predominating in the male and ACOT2 in the female. These findings validate the genetic model and highlight insights to be gained through targeted profiling of adipocytes. The genetic tool adds to existing approaches for in vivo proximity profiling of cell-type specific proteome programs.

Keywords:  adipocytes; adipose tissue; mouse model; proteomics; proximity labeling

DOI:  https://doi.org/10.1002/cph4.70007
Nat Commun. 2025 Apr 01. 16(1): 3111

Exercise-induced anti-obesity effects in male mice generated by a FOXO1-KLF10 reinforcing loop promoting adipose lipolysis.

Jie-Ying Zhu, Min Chen, Wang-Jing Mu, Hong-Yang Luo, Yang Li, Shan Li, Lin-Jing Yan, Ruo-Ying Li, Meng-Ting Yin, Xin Li, Hu-Min Chen, Liang Guo.

Exercise combats obesity and metabolic disorders, but the underlying mechanism is incompletely understood. KLF10, a transcription factor involved in various biological processes, has an undefined role in adipose tissue and obesity. Here, we show that exercise facilitates adipocyte-derived KLF10 expression via SIRT1/FOXO1 pathway. Adipocyte-specific knockout of KLF10 blunts exercise-promoted white adipose browning, energy expenditure, fat loss, glucose tolerance in diet-induced obese male mice. Conversely, adipocyte-specific transgenic expression of KLF10 in male mice enhanced the above metabolic profits induced by exercise. Mechanistically, KLF10 interacts with FOXO1 and facilitates the recruitment of KDM4A to form a ternary complex on the promoter regions of Pnpla2 and Lipe genes to promote these key lipolytic genes expression by demethylating H3K9me3 on their promoters, which facilitates lipolysis to defend against obesity in male mice. As a downstream effector responding to exercise, adipose KLF10 could act as a potential target in the fight against obesity.

DOI: https://doi.org/10.1038/s41467-025-58467-1
bioRxiv. 2025 Mar 19. pii: 2025.03.18.644013. [Epub ahead of print]

Setdb2 Regulates Inflammatory Trigger-Induced Trained Immunity of Macrophages Through Two Different Epigenetic Mechanisms.

Anant Jaiswal, Laszlo Halasz, David L Williams, Timothy Osborne.

"Trained immunity" of innate immune cells occurs through a sequential two-step process where an initial pathogenic or sterile inflammatory trigger is followed by an amplified response to a later un-related secondary pathogen challenge. The memory effect is mediated at least in part through epigenetic modifications of the chromatin landscape. Here, we investigated the role of the epigenetic modifier Setdb2 in microbial (β-glucan) or sterile trigger (Western-diet-WD/oxidized-LDL-oxLDL)-induced trained immunity of macrophages. Using genetic mouse models and genomic analysis, we uncovered a critical role of Setdb2 in regulating proinflammatory and metabolic pathway reprogramming. We further show that Setdb2 regulates trained immunity through two different complementary mechanisms: one where it positively regulates glycolytic and inflammatory pathway genes via enhancer-promoter looping, and is independent of its enzymatic activity; while the second mechanism is associated with both increased promoter associated H3K9 methylation and repression of interferon response pathway genes. Interestingly, while both mechanisms occur in response to pathogenic training, only the chromatin-looping mechanism operates in response to the sterile inflammatory stimulus. These results reveal a previously unknown bifurcation in the downstream pathways that distinguishes between pathogenic and sterile inflammatory signaling responses associated with the innate immune memory response and may provide potential therapeutic opportunities to target cytokine vs. interferon pathways to limit complications of chronic inflammation.

DOI: https://doi.org/10.1101/2025.03.18.644013
Metabolism. 2025 Mar 26. pii: S0026-0495(25)00108-8. [Epub ahead of print]168 156239

The serine protease KLK7 promotes immune cell infiltration in visceral adipose tissue in obesity.

Aleix Ribas-Latre, Anne Hoffmann, Claudia Gebhardt, Juliane Weiner, Lilli Arndt, Nora Raulien, Martin Gericke, Adhideb Ghosh, Kerstin Krause, Nora Klöting, Paul T Pfluger, Bilal N Sheikh, Thomas Ebert, Anke Tönjes, Michael Stumvoll, Christian Wolfrum, Matthias Blüher, Ulf Wagner, Joan Vendrell, Sonia Fernández-Veledo, John T Heiker.

  Obesity is a major health problem associated with global metabolic dysfunction and increased inflammation. It is thus critical to identify the mechanisms underlying the crosstalk between immune cells and adipose tissue that drive cardiovascular and metabolic dysfunction in obesity. Expression of the kallikrein-related serine protease 7 (KLK7) in adipose tissue is linked to inflammation and insulin resistance in high fat diet (HFD)-fed mice. Here, we engineered mice with a macrophage-specific KLK7 knockout (KLK7MKO) to investigate how KLK7 loss impacts immune cell function and obesity-related pathology. Compared to control mice, we observed lower levels of systemic inflammation, with less infiltration and activation of inflammatory macrophages in HFD-fed KLK7MKO mice, particularly in the epididymal adipose tissue. Mechanistically, we uncover that Klk7 deficiency reduces pro-inflammatory gene expression in macrophages and restricts their migration through higher cell adhesion, hallmark features of macrophages in obese conditions. Importantly, through analyses of 1143 human visceral adipose tissue samples, we uncover that KLK7 expression is associated with pathways controlling cellular migration and inflammatory gene expression. In addition, serum KLK7 levels were strongly correlated with circulating inflammatory markers in a second cohort of 60 patients with obesity and diabetes. Our work uncovers the pro-inflammatory role of KLK7 in controlling inflammatory macrophage polarization and infiltration in visceral obesity, thereby contributing to metabolic disease. Thus, targeting KLK7 to control immune cell activation may dissociate adipose dysfunction from obesity, thereby representing an alternative obesity therapy.

Keywords:  Adipose tissue; Inflammation; Metabolic disease; Obesity; Protease; Serpin

DOI:  https://doi.org/10.1016/j.metabol.2025.156239
Bone Res. 2025 Apr 02. 13(1): 43

KIAA1199 (CEMIP) regulates adipogenesis and whole-body energy metabolism.

Li Chen, Kaikai Shi, Nicholas Ditzel, Weimin Qiu, Michaela Tencerova, Louise Himmelstrup Dreyer Nielsen, Florence Figeac, Alexander Rauch, Yuhang Liu, Jiuyuan Tao, Veronika Sramkova, Lenka Rossmeislova, Greet Kerckhofs, Tatjana N Parac-Vogt, Sébastien de Bournonville, Thomas Levin Andersen, Mikael Rydén, Moustapha Kassem.

An increasing number of studies have characterized the bone as an endocrine organ, and that bone secreted factors may not only regulate local bone remodeling, but also other tissues and whole-body metabolic functions. The precise nature of these regulatory factors and their roles at bridging the bone, bone marrow adipose tissue, extramedullary body fat and whole-body energy homeostasis are being explored. In this study, we report that KIAA1199, a secreted factor produced from bone and bone marrow, previously described as an inhibitor of bone formation, also plays a role at promoting adipogenesis. KIAA1199-deficient mice exhibit reduced bone marrow adipose tissue, subcutaneous and visceral fat tissue mass, blood cholesterol, triglycerides, free fatty acids and glycerol, as well as improved insulin sensitivity in skeletal muscle, liver and fat. Moreover, these mice are protected from the detrimental effects of high-fat diet feeding, with decreased obesity, lower blood glucose and glucose tolerance, as well as decreased adipose tissue inflammation, insulin resistance and hepatic steatosis. In human studies, plasma levels of KIAA1199 or its expression levels in adipose tissue are positively correlated with insulin resistance and blood levels of cholesterol, triglycerides, free fatty acids, glycerol, fasting glucose and HOMA-IR. Mechanistically, KIAA1199 mediates its effects on adipogenesis through modulating osteopontin-integrin and AKT / ERK signaling. These findings provide evidence for the role of bone secreted factors on coupling bone, fat and whole-body energy homeostasis.

DOI: https://doi.org/10.1038/s41413-025-00415-2
Adv Sci (Weinh). 2025 Apr 04. e2501055

The FGF13-Caveolin-1 Axis: A Key Player in the Pathogenesis of Doxorubicin- and D-Galactose-Induced Premature Cardiac Aging.

Enzhao Shen, Yuecheng Wu, Weijian Ye, Sihang Li, Junjie Zhu, Meifan Jiang, Zhicheng Hu, Gaoyong Cao, Xiaojing Yi, Fan Li, Zhouhao Tang, Xiaokun Li, Kwang Youl Lee, Litai Jin, Xu Wang, Weitao Cong.

  Delaying senescence of cardiomyocytes has garnered widespread attention as a potential target for preventing cardiovascular diseases (CVDs). FGF13 (Fibroblast growth factor 13) has been implicated in various pathophysiological processes. However, its role in premature myocardial aging and cardiomyocyte senescence remains unknown. Adeno-associated virus 9 (AAV9) vectors expressing FGF13 and cardiac-specific Fgf13 knockout (Fgf13KO) mice are utilized to reveal that FGF13 overexpression and deficiency exacerbated and alleviated Doxorubicin/D-galactose-induced myocardial aging characteristics and functional impairment, respectively. Transcriptomics are employed to identify an association between FGF13 and Caveolin-1 (Cav1). Mechanistic studies indicated that FGF13 regulated the Cav1 promoter activity and expression through the p38/MAPK pathway and nuclear translocation of p65, as well as the binding level of PTRF to Cav1 to mediate cardiomyocyte senescence. Furthermore, Cav1 overexpression in murine hearts reversed the alleviatory effects of FGF13 deficiency on the Doxorubicin/D-galactose-induced myocardial aging phenotype and dysfunction. This study has demonstrated that FGF13 regulated the Cav1-p53-p21 axis to augment cardiomyocyte senescence and thereby exacerbated cardiac premature aging and suggests that FGF13 knockdown may be a promising approach to combat CVDs in response to aging and chemotoxicity.

Keywords:  cardiac premature aging; cardiomyocyte senescence; caveolin‐1; fibroblast growth factor 13; p53 signaling

DOI:  https://doi.org/10.1002/advs.202501055
Sci Adv. 2025 Apr 04. 11(14): eadq1575

Atf3 controls transitioning in female mitochondrial cardiomyopathy as identified by spatial and single-cell transcriptomics.

Tasneem Qaqorh, Yusuke Takahashi, Kohei Sameshima, Kentaro Otani, Issei Yazawa, Yuya Nishida, Kohei Tonai, Yoshitaka Fujihara, Mizuki Honda, Shinya Oki, Yasuyuki Ohkawa, David R Thorburn, Ann E Frazier, Atsuhito Takeda, Yoshihiko Ikeda, Heima Sakaguchi, Takuya Watanabe, Norihide Fukushima, Yasumasa Tsukamoto, Naomasa Makita, Osamu Yamaguchi, Kei Murayama, Akira Ohtake, Yasushi Okazaki, Takanari Kimura, Hisakazu Kato, Hijiri Inoue, Ken Matsuoka, Seiji Takashima, Yasunori Shintani.

Oxidative phosphorylation defects result in now intractable mitochondrial diseases (MD) with cardiac involvement markedly affecting prognosis. The mechanisms underlying the transition from compensation to dysfunction in response to metabolic deficiency remain unclear. Here, we used spatially resolved transcriptomics and single-nucleus RNA sequencing (snRNA-seq) on the heart of a patient with mitochondrial cardiomyopathy (MCM), combined with an MCM mouse model with cardiac-specific Ndufs6 knockdown (FS6KD). Cardiomyocytes demonstrated the most heterogeneous expression landscape among cell types caused by metabolic perturbation, and pseudotime trajectory analysis revealed dynamic cellular states transitioning from compensation to severe compromise. This progression coincided with the transient up-regulation of a transcription factor, ATF3. Genetic ablation of Atf3 in FS6KD corroborated its pivotal role, effectively delaying cardiomyopathy progression in a female-specific manner. Our findings highlight a fate-determining role of ATF3 in female MCM progression and that the latest transcriptomic analysis will help decipher the mechanisms underlying MD progression.

DOI: https://doi.org/10.1126/sciadv.adq1575
Cell Metab. 2025 Mar 24. pii: S1550-4131(25)00107-X. [Epub ahead of print]

Gang of 3: How the Krebs cycle-linked metabolites itaconate, succinate, and fumarate regulate macrophages and inflammation.

Eva M Pålsson-McDermott, Luke A J O'Neill.

  The reprogramming of metabolic pathways and processes in immune cells has emerged as an important aspect of the immune response. Metabolic intermediates accumulate as a result of metabolic adaptations and mediate functions outside of metabolism in the regulation of immunity and inflammation. In macrophages, there has been a major focus on 3 metabolites linked to the Krebs cycle, itaconate, succinate, and fumarate, which have been shown to regulate multiple processes. Here, we discuss recent progress on these 3 metabolites with regard to their effect on macrophages in host defense and inflammatory diseases. We also consider the therapeutic opportunities presented from the mimicry of these metabolites or by targeting the enzymes that make or metabolize them in order to leverage the body's own anti-inflammatory response.

Keywords:  ETC; Krebs cycle; immunometabolism; immunometabolites; inflammation; therapeutic targets

DOI:  https://doi.org/10.1016/j.cmet.2025.03.004
Epigenetics Chromatin. 2025 Mar 29. 18(1): 16

Crosstalk between metabolism and epigenetics during macrophage polarization.

Kangling Zhang, Chinnaswamy Jagannath.

  Macrophage polarization is a dynamic process driven by a complex interplay of cytokine signaling, metabolism, and epigenetic modifications mediated by pathogens. Upon encountering specific environmental cues, monocytes differentiate into macrophages, adopting either a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype, depending on the cytokines present. M1 macrophages are induced by interferon-gamma (IFN-γ) and are characterized by their reliance on glycolysis and their role in host defense. In contrast, M2 macrophages, stimulated by interleukin-4 (IL-4) and interleukin-13 (IL-13), favor oxidative phosphorylation and participate in tissue repair and anti-inflammatory responses. Metabolism is tightly linked to epigenetic regulation, because key metabolic intermediates such as acetyl-coenzyme A (CoA), α-ketoglutarate (α-KG), S-adenosylmethionine (SAM), and nicotinamide adenine dinucleotide (NAD+) serve as cofactors for chromatin-modifying enzymes, which in turn, directly influences histone acetylation, methylation, RNA/DNA methylation, and protein arginine methylation. These epigenetic modifications control gene expression by regulating chromatin accessibility, thereby modulating macrophage function and polarization. Histone acetylation generally promotes a more open chromatin structure conducive to gene activation, while histone methylation can either activate or repress gene expression depending on the specific residue and its methylation state. Crosstalk between histone modifications, such as acetylation and methylation, further fine-tunes macrophage phenotypes by regulating transcriptional networks in response to metabolic cues. While arginine methylation primarily functions in epigenetics by regulating gene expression through protein modifications, the degradation of methylated proteins releases arginine derivatives like asymmetric dimethylarginine (ADMA), which contribute directly to arginine metabolism-a key factor in macrophage polarization. This review explores the intricate relationships between metabolism and epigenetic regulation during macrophage polarization. A better understanding of this crosstalk will likely generate novel therapeutic insights for manipulating macrophage phenotypes during infections like tuberculosis and inflammatory diseases such as diabetes.

Keywords:  Acetylation; Epigenetics; Glucose metabolism; Histones; IFN-γ; IL-13; IL-4; IL10; M1; M2; Macrophage polarization; Macrophages; Metabolism; Methylation; Sirtuins

DOI:  https://doi.org/10.1186/s13072-025-00575-9
Nat Struct Mol Biol. 2025 Apr 02.

O-GlcNAc transferase is a key regulator of DNA methylation and transposon silencing.

DOI: https://doi.org/10.1038/s41594-025-01507-7
Life Sci Alliance. 2025 Jun;pii: e202402921. [Epub ahead of print]8(6):

The MFN2 Q367H variant reveals a novel pathomechanism connected to mtDNA-mediated inflammation.

Mashiat Zaman, Govinda Sharma, Walaa Almutawa, Tyler Gb Soule, Rasha Sabouny, Matt Joel, Armaan Mohan, Cole Chute, Jeffrey T Joseph, Gerald Pfeffer, Timothy E Shutt.

Pathogenic variants in the mitochondrial protein MFN2 are typically associated with a peripheral neuropathy phenotype, but can also cause a variety of additional pathologies including myopathy. Here, we identified an uncharacterized MFN2 variant, Q367H, in a patient diagnosed with late-onset distal myopathy, but without peripheral neuropathy. Supporting the hypothesis that this variant contributes to the patient's pathology, patient fibroblasts and transdifferentiated myoblasts showed changes consistent with impairment of several MFN2 functions. We also observed mtDNA outside of the mitochondrial network that colocalized with early endosomes, and measured activation of both TLR9 and cGAS-STING inflammation pathways that sense mtDNA. Re-expressing the Q367H variant in MFN2 KO cells also induced mtDNA release, demonstrating this phenotype is a direct result of the variant. As elevated inflammation can cause myopathy, our findings linking the Q367H MFN2 variant with elevated TLR9 and cGAS-STING signalling can explain the patient's myopathy. Thus, we characterize a novel MFN2 variant in a patient with an atypical presentation that separates peripheral neuropathy and myopathy phenotypes, and establish a potential pathomechanism connecting MFN2 dysfunction to mtDNA-mediated inflammation.

DOI: https://doi.org/10.26508/lsa.202402921
Nat Struct Mol Biol. 2025 Mar 28.

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide.

Hugo Sepulveda, Xiang Li, Leo J Arteaga-Vazquez, Isaac F López-Moyado, Melina Brunelli, Lot Hernández-Espinosa, Xiaojing Yue, J Carlos Angel, Caitlin Brown, Zhen Dong, Natasha Jansz, Fabio Puddu, Aurélie Modat, Jamie Scotcher, Páidí Creed, Patrick H Kennedy, Cindy Manriquez-Rodriguez, Samuel A Myers, Robert Crawford, Geoffrey J Faulkner, Anjana Rao.

O-GlcNAc transferase (OGT) interacts robustly with all three mammalian TET methylcytosine dioxygenases. Here we show that deletion of the Ogt gene in mouse embryonic stem (mES) cells results in a widespread increase in the TET product 5-hydroxymethylcytosine in both euchromatic and heterochromatic compartments, with a concomitant reduction in the TET substrate 5-methylcytosine at the same genomic regions. mES cells treated with an OGT inhibitor also displayed increased 5-hydroxymethylcytosine, and attenuating the TET1-OGT interaction in mES cells resulted in a genome-wide decrease of 5-methylcytosine, indicating that OGT restrains TET activity and limits inappropriate DNA demethylation in a manner that requires the TET-OGT interaction and the catalytic activity of OGT. DNA hypomethylation in OGT-deficient cells was accompanied by derepression of transposable elements predominantly located in heterochromatin. We suggest that OGT protects the genome against TET-mediated DNA demethylation and loss of heterochromatin integrity, preventing the aberrant increase in transposable element expression noted in cancer, autoimmune-inflammatory diseases, cellular senescence and aging.

DOI: https://doi.org/10.1038/s41594-025-01505-9
Front Physiol. 2025 ;16 1562848

Role of genetic variants and DNA methylation of lipid metabolism-related genes in metabolic dysfunction-associated steatotic liver disease.

Jun-Jie Wang, Xiao-Yuan Chen, Yi-Rong Zhang, Yan Shen, Meng-Lin Zhu, Jun Zhang, Jun-Jie Zhang.

  Metabolic dysfunction-associated steatotic liver disease (MASLD), is one of the most common chronic liver diseases, which encompasses a spectrum of diseases, from metabolic dysfunction-associated steatotic liver (MASL) to metabolic dysfunction-associated steatohepatitis (MASH), and may ultimately progress to MASH-related cirrhosis and hepatocellular carcinoma (HCC). MASLD is a complex disease that is influenced by genetic and environmental factors. Dysregulation of hepatic lipid metabolism plays a crucial role in the development and progression of MASLD. Therefore, the focus of this review is to discuss the links between the genetic variants and DNA methylation of lipid metabolism-related genes and MASLD pathogenesis. We first summarize the interplay between MASLD and the disturbance of hepatic lipid metabolism. Next, we focus on reviewing the role of hepatic lipid related gene loci in the onset and progression of MASLD. We summarize the existing literature around the single nucleotide polymorphisms (SNPs) associated with MASLD identified by genome-wide association studies (GWAS) and candidate gene analyses. Moreover, based on recent evidence from human and animal studies, we further discussed the regulatory function and associated mechanisms of changes in DNA methylation levels in the occurrence and progression of MASLD, with a particular emphasis on its regulatory role of lipid metabolism-related genes in MASLD and MASH. Furthermore, we review the alterations of hepatic DNA and blood DNA methylation levels associated with lipid metabolism-related genes in MASLD and MASH patients. Finally, we introduce potential value of the genetic variants and DNA methylation profiles of lipid metabolism-related genes in developing novel prognostic biomarkers and therapeutic targets for MASLD, intending to provide references for the future studies of MASLD.

Keywords:  DNA methylation; biomarker; genetic variant; lipid metabolism; metabolic dysfunction-associated steatohepatitis (MASH); metabolic dysfunction-associated steatotic liver disease (MASLD)

DOI:  https://doi.org/10.3389/fphys.2025.1562848
Nat Aging. 2025 Mar 31.

Invigorating discovery and clinical translation of aging biomarkers.

Erik Jacques, Chiara Herzog, Kejun Ying, Alan Tomusiak, Jessica Kasamoto, Raghav Sehgal, Seth Paulson, Julian Reinhard, Jakob Träuble, Waylon J Hastings, Alexander Tyshkovskiy, Sara Hägg, John C Earls, Christian E Behrens, Jessica Lasky-Su, Gavin Zhou, Eric Morgen, John S Tsang, Riccardo E Marioni, Xiao-Jun Ma, Alexandra Stolzing, Christin Glorioso, Jonathan S Gootenberg, Omar O Abudayyeh, M Austin Argentieri, Raymond H Mak, Lynne S Cox, Andrew S Brack, Gordan Lauc, David Furman, Jason D Buenrostro, Björn Schumacher, Jamie N Justice, Tina Woods, David Gobel, Viviana I Perez, David A Sinclair, Andrea B Maier, Nir Barzilai, Michael P Snyder, Tony Wyss-Coray, Steve Horvath, Luigi Ferrucci, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev.

DOI: https://doi.org/10.1038/s43587-025-00838-w
Nat Commun. 2025 Apr 01. 16(1): 3101

Integration of GWAS, QTLs and keratinocyte functional assays reveals molecular mechanisms of atopic dermatitis.

Meritxell Oliva, Mrinal K Sarkar, Michael E March, Amir Hossein Saeidian, Frank D Mentch, Chen-Lin Hsieh, Fanying Tang, Ranjitha Uppala, Matthew T Patrick, Qinmengge Li, Rachael Bogle, J Michelle Kahlenberg, Deborah Watson, Joseph T Glessner, Leila Youssefian, Hassan Vahidnezhad, Lam C Tsoi, Hakon Hakonarson, Johann E Gudjonsson, Kathleen M Smith, Bridget Riley-Gillis.

Atopic dermatitis is a highly heritable and common inflammatory skin condition affecting children and adults worldwide. Multi-ancestry approaches to atopic dermatitis genetic association studies are poised to boost power to detect genetic signal and identify loci contributing to atopic dermatitis risk. Here, we present a multi-ancestry GWAS meta-analysis of twelve atopic dermatitis cohorts from five ancestral populations totaling 56,146 cases and 602,280 controls. We report 101 genomic loci associated with atopic dermatitis, including 16 loci that have not been previously associated with atopic dermatitis or eczema. Fine-mapping, QTL colocalization, and cell-type enrichment analyses identified genes and cell types implicated in atopic dermatitis pathophysiology. Functional analyses in keratinocytes provide evidence for genes that could play a role in atopic dermatitis through epidermal barrier function. Our study provides insights into the etiology of atopic dermatitis by harnessing multiple genetic and functional approaches to unveil the mechanisms by which atopic dermatitis-associated variants impact genes and cell types.

DOI: https://doi.org/10.1038/s41467-025-58310-7
Cell Rep. 2025 Mar 28. pii: S2211-1247(25)00255-4. [Epub ahead of print]44(4): 115484

PRMT5-mediated methylation of METTL3 promotes cisplatin resistance in ovarian cancer by facilitating DNA repair mechanisms.

Qiaoxi Xia, Ronghui Zhong, Jingfang Zheng, Xiao Zhou, Xinwei Zhao, Sisi Wang, Botao Wang, Quanfeng Wu, Chen Xie, Beihua Kong, Qing Zhang, Tianzhi Huang.

  Cisplatin (CDDP) is a widely used chemotherapy drug for treating various solid tumors. However, resistance to CDDP significantly hampers patient outcomes. This study reveals that protein arginine methyltransferase (PRMT)5 methylates METTL3 at the R36 residue (METTL3-R36me2), which is crucial for CDDP resistance in ovarian cancer (OC) cells. Following CDDP exposure, MST4 is transactivated by nuclear factor-erythroid 2-related factor 2 (NRF2), a key regulator of antioxidant responses. MST4 stimulates PRMT5's methyltransferase activity and promotes its interaction with METTL3 via phosphorylation at Ser439 and Ser463, resulting in increased levels of METTL3-R36me2 and mRNA methylation at the N6 position of adenosine (m6A). The METTL3-R36me2 is recruited to DNA damage sites to promote RAD51 recruitment for homologous recombination (HR)-mediated double-strand break repair (DSBR) and enhance CDDP resistance. Importantly, targeting METTL3-R36me2 through inhibition of PRMT5 or METTL3 disrupts HR-DSBR and augments the cytotoxic effects of CDDP in ovarian tumor xenografts. Therefore, we conclude that METTL3-R36me2 represents a viable therapeutic target for overcoming CDDP resistance in OC.

Keywords:  CP: Cancer; CP: Molecular biology; DNA repair; METTL3; MST4; NRF2; PRMT5; arginine methylation; cisplatin; ovarian cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.115484