Biochimica et Biophysica Acta-Gene Regulatory Mechanisms最新文献

{"title":"SALL4 drives gastric cancer progression through PI3K/Akt-mediated regulation of glycolysis, EMT, stemness, and adhesion remodeling.","authors":"Yuan Jin, Chao Hu, Xiaokang Shi","doi":"10.1016/j.bbagrm.2026.195192","DOIUrl":"https://doi.org/10.1016/j.bbagrm.2026.195192","url":null,"abstract":"<p><p>SALL4 has emerged as an oncogenic driver in multiple malignancies; however, its role in gastric cancer (GC) is insufficiently defined. This paper was conceived to elucidate the functional significance as well as to uncover the downstream mechanisms of SALL4 in GC progression. SALL4 expression in GC tissues and its prognostic significance were processed via bioinformatics datasets, RT-qPCR, western blot, and IHC staining. Functional assays, including CCK-8, colony formation, migration, invasion, adhesion, and spheroid formation, were performed in GC cell lines following SALL4 knockdown or overexpression. Glycolytic activity was evaluated by ECAR, OCR, glucose uptake, and lactate production. The involvement of the PI3K/Akt pathway and its downstream effectors, including β-catenin, FAK-YAP and HIF-1α was examined using pathway inhibitors and rescue experiments. HIF-1 transcriptional activity and downstream target gene expression were further assessed using an HRE-driven dual-luciferase reporter assay and RT-qPCR, respectively. Elevated SALL4 expression was observed in GC samples and was positively associated with advanced TNM classification, nodal metastasis, and poor clinical outcomes. Silencing of SALL4 suppressed GC cell growth, motility, invasiveness, EMT progression, stemness maintenance, adhesive capacity, cytoskeletal dynamics, and glycolysis, while overexpression produced the opposite effects. Mechanistically, SALL4 activated the PI3K/Akt pathway, resulting in β-catenin upregulation that promoted EMT and stemness, FAK-YAP activation that enhanced adhesion and cytoskeleton, and HIF-1α induction that facilitated glycolytic reprogramming. Pathway inhibition and rescue experiments supported the involvement of PI3K/Akt and its downstream effectors in selected SALL4-associated phenotypes. Our findings support a potential role for SALL4 in regulating GC cell phenotypic plasticity and metabolic reprogramming through the PI3K/Akt signaling pathway. The SALL4/PI3K/Akt axis represents a candidate molecular pathway warranting further investigation, while its therapeutic applicability remains to be established through dedicated preclinical intervention studies and validation in appropriate in vivo and patient-derived models.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 4","pages":"195192"},"PeriodicalIF":3.6,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149327694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Balancing miRNA silencing: Ubiquitin-mediated control of Dicer and Argonaute.","authors":"Mason Waye, Victoria Sutto, Pavan Kumar Kakumani","doi":"10.1016/j.bbagrm.2026.195191","DOIUrl":"https://doi.org/10.1016/j.bbagrm.2026.195191","url":null,"abstract":"<p><p>Dicer and Argonaute proteins are core effectors of the miRNA pathway and are essential for cellular homeostasis. This review synthesizes recent advances in the mechanisms that control their stability and function, with a focus on post-translational regulation. Dicer is targeted for degradation via proteasomal and lysosomal pathways, modulating miRNA biogenesis, and multiple E3 ligases regulate its stability across biological contexts. Argonaute proteins are similarly regulated to control miRNA function, with Argonaute 2 exhibiting context-dependent modulation under hypoxia and acute liver injury, including target-directed miRNA degradation. Together, these mechanisms define a ubiquitin-mediated regulatory layer shaping miRNA output in physiology and disease.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195191"},"PeriodicalIF":3.6,"publicationDate":"2026-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149327693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of EZH2 increases oral epithelial cell stress responses.","authors":"Jorge Baquero, Xiao-Han Tang, Tuo Zhang, Eduardo Mere Del Aguila, Lorraine J Gudas","doi":"10.1016/j.bbagrm.2026.195189","DOIUrl":"10.1016/j.bbagrm.2026.195189","url":null,"abstract":"<p><p>Enhancer of zeste homolog 2 (EZH2), a member of polycomb repressive complex 2 (PRC2), is expressed in almost all basal stem cells (SCs) of the epithelial lining of the tongue. We previously generated a transgenic mouse model (KcEZH2) containing a tamoxifen (tam) dependent CreER system to selectively knock out (KO) EZH2 (KcEZH2-T) in most tongue basal epithelial SCs. Here, we used this model to assess EZH2 actions in normal tongue epithelia. Genome-wide transcriptomics revealed that signaling pathways associated with stress responses were increased, whereas cell-cycle-related processes and cell proliferation were decreased in KcEZH2-T oral epithelia. Indeed, EZH2 KO increased the expression of EGR1, BTG2, c-Fos, and c-Jun proteins, which are products of immediate-early genes (IEGs) associated with cellular responses during various types of cell stress, and decreased Ki67 protein. Our chromatin immunoprecipitation (ChIP) data in tongue epithelia of wild type mice showed that the chromatin near specific regions of the Egr1, Btg2, and Fos genes displayed H3K27me3 marks, the epigenetic modification catalyzed by EZH2 in canonical PRC2 complex assemblies. We additionally found that Loricrin and E-cadherin proteins were increased in KcEZH2-T vs. KcEZH2 oral epithelia. Thus, our data demonstrate that deletion of EZH2 increases stress-related responses in normal tongue epithelia. As previous studies show that IEGs are increased while cell cycle progression is suppressed in early stages of wound repair, transiently inhibiting EZH2 expression and function warrants further investigation as a hypothetical framework for innovative wound healing approaches.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195189"},"PeriodicalIF":3.6,"publicationDate":"2026-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149302061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"M6A-modified lncRNA RMRP facilitates mitophagy and promotes ox-LDL-induced endothelial cell injury by interacting with PTBP1 and activating the PI3K/AKT pathway.","authors":"Ying Fu, Zhu Zhang, Yanqin Yu, Yuanmin Chai, Jinqi Hao, Qinghong Qiao","doi":"10.1016/j.bbagrm.2026.195190","DOIUrl":"https://doi.org/10.1016/j.bbagrm.2026.195190","url":null,"abstract":"<p><strong>Background: </strong>Endothelial cell dysfunction has been identified as a major risk factor for atherosclerosis. The long non-coding RNA (LncRNA) RNA component of mitochondrial RNA processing endoribonuclease (RMRP) has been detected in mitochondria and is closely associated with inflammation and autophagy. However, the role of the lncRNA RMRP in endothelial cell injury and its potential molecular mechanisms remain unclear.</p><p><strong>Methods: </strong>Mouse aortic endothelial cells (MAECs) were treated with oxidised low-density lipoprotein (ox-LDL). Changes in cell viability, proinflammatory cytokine levels, mitophagy, and mitochondrial membrane potential in MAECs were assessed to investigate the effects of lncRNA RMRP and protein kinase B (AKT3) on endothelial injury. Knockdown and overexpression experiments were performed to determine the effects of lncRNA RMRP, polypyrimidine tract-binding protein 1 (PTBP1), and AKT3 on MAECs stimulated with ox-LDL.</p><p><strong>Results: </strong>Ox-LDL markedly reduced cell viability, increased proinflammatory factor levels, induced mitophagy, and reduced mitochondrial membrane potential in MAECs. Knockdown of lncRNA RMRP attenuated ox-LDL-induced inflammatory responses and mitophagy in MAECs. Knockdown of Methyltransferase-like 14 (METTL14) suppressed the expression of lncRNA RMRP through m6A modification in ox-LDL-treated MAECs. LncRNA RMRP enhanced AKT3 mRNA stability by interacting with PTBP1. LncRNA RMRP promoted ox-LDL-induced mitophagy by targeting AKT3 and stimulating the Phosphatidylinositol 3-kinase (PI3K)/AKT pathway in MAECs.</p><p><strong>Conclusion: </strong>METTL14 regulates the expression of lncRNA RMRP through m6A modification. Overexpressed lncRNA RMRP targets AKT3 by recruiting PTBP1, thus activating the PI3K/AKT pathway to mediate mitophagy and promote the progression of atherosclerosis.</p>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":" ","pages":"195190"},"PeriodicalIF":3.6,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149290281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of two forms of the calcium/calmodulin-dependent protein kinase Cmk2 is differentially regulated in response to calcium stress in budding yeast","authors":"Linghuo Jiang ,&nbsp;Liudan Wei ,&nbsp;Yiying Gu ,&nbsp;Peigen Jiang ,&nbsp;Nathan Snyder ,&nbsp;Xiufan Liao ,&nbsp;Yiping Mo ,&nbsp;Lingxin Pan ,&nbsp;Chunyu Wei ,&nbsp;Kyle W. Cunningham","doi":"10.1016/j.bbagrm.2025.195122","DOIUrl":"10.1016/j.bbagrm.2025.195122","url":null,"abstract":"<div><div>Cmk2 is a homolog of mammalian calcium/calmodulin-dependent protein kinase II (CaMKII), and functions as a negative regulator of calcium signaling in yeast cells. Transcription of <em>CMK2</em> gene is controlled by the zinc finger transcription factor Crz1 via a CDRE motif in the promoter. In this study, we have characterized the protein expression and phosphorylation of Cmk2. Purified Cmk2 proteins from yeast cells undergo autophosphorylation. Two forms of Cmk2 proteins, the <u>s</u>low-<u>m</u>igrating (SM-Cmk2) and the <u>f</u>ast-<u>m</u>igrating (FM-Cmk2), were detected in response of yeast cells to calcium stress. In the absence of calcium stress, Cmk2 appears to be mainly in the form of SM-Cmk2. Deletion of <em>CNB1</em> delays the calcium-induction of both forms, but only reduces the level of the calcium-induced FM-Cmk2. An extracellular calcium concentration of 200 mM results in maximal induction of both forms of Cmk2. Therefore, in addition to calcium/calcineurin signaling, expression of Cmk2 protein is controlled by additional factor(s). Furthermore, our mutational analysis indicates that the K76 residue of Cmk2 is required for the calcium-induction and steady-state expression levels of both FM-Cmk2 and SM-Cmk2. The S317 residue, the counterpart of the O-linked glycosylation site S279 in mammalian CaMKII, is also responsible for the calcium-induction of SM-Cmk2.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195122"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145594782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen produced in the retina by brain aromatase plays a significant role in zebrafish eye development","authors":"Zulvikar Syambani Ulhaq ,&nbsp;Mitsuyo Kishida","doi":"10.1016/j.bbagrm.2025.195133","DOIUrl":"10.1016/j.bbagrm.2025.195133","url":null,"abstract":"<div><div>Aromatase is a key enzyme in estrogen biosynthesis, expressed in multiple tissues including the brain and retina. In teleost fish, Aromatase B (AroB), encoded by <em>cyp19a1b</em>, is brain-specific and highly expressed during early development, suggesting a role in neurogenesis. Here, we investigated the role of AroB in zebrafish eye development using morpholino (MO)-mediated knockdown. Injection of AroB MO into fertilized eggs reduced eye size (eye-to-body length ratio), decreased optic nerve diameter at 48 h post-fertilization (hpf), and increased apoptosis in the eye at 24 hpf. These defects were rescued by co-injection of AroB mRNA or treatment with 1 μM 17β-estradiol (E₂). Functional assays revealed impaired visual background adaptation (VBA) at 5 days post-fertilization (dpf) and defective optomotor response (OMR) at 7 dpf in AroB morphants. Immunostaining with AroB antiserum confirmed a reduction in retinal AroB expression in knockdown larvae. To assess the role of estrogen receptors (ERs), embryos were exposed to selective antagonists. The ERα antagonist MPP had no effect on eye size, optic nerve diameter, or apoptosis. In contrast, the ERβ antagonist CYC reduced eye size and optic nerve diameter, while increasing apoptosis. The non-selective ER antagonist ICI also reduced eye size and elevated apoptosis, though it did not alter optic nerve diameter. Behaviorally, VBA was reduced by ICI and CYC, but not MPP; OMR was diminished by ICI and MPP, but unaffected by CYC. Together, these findings demonstrate that estrogen produced in the retina by AroB plays a critical role in zebrafish eye development, with its functions differentially mediated by distinct ER subtypes.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195133"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of novel post-translational modifications in the male reproductive system: From regulation of reproductive development to therapeutic potential","authors":"Xin-Rong Du ,&nbsp;Yan Gao ,&nbsp;Qin Zeng ,&nbsp;Guo-Hui Zhang ,&nbsp;Wei-Xin Liu","doi":"10.1016/j.bbagrm.2025.195132","DOIUrl":"10.1016/j.bbagrm.2025.195132","url":null,"abstract":"<div><div>Post-translational modifications (PTMs) play a pivotal role in understanding male reproductive function, with an increasing number of PTMs being demonstrated to be associated with spermatogenesis and sperm function. The advancement of high-throughput molecular tools and the accumulation of bioinformatics data have significantly accelerated the discovery of novel PTMs. In this review, we highlight several newly identified PTMs, these modifications participate in spermatogenesis, sperm maturation, sperm motility in the female reproductive tract, capacitation, fertilization, as well as the regulation of Sertoli cell and epididymal functions. Furthermore, we discuss their involvement in the pathogenesis of various conditions, including asthenozoospermia, erectile dysfunction, and even testicular and prostate cancers, while exploring their potential clinical applications as therapeutic targets and biomarkers. Additionally, we provide insights into the cooperative or competitive interactions among different types of PTMs. A comprehensive understanding of PTM-mediated regulatory mechanisms in the male reproductive system will pave the way for developing novel and specific therapeutic strategies to treat male reproductive disorders. A systematic literature search was performed in PubMed, MEDLINE, EMBASE, and Web of Science Core Collection for studies published up to September 2025, using a combination of the term “male Reproductive System, sperm, fertilization, capacitation, disease” with keywords related to post-translational modifications, Eligible studies were limited to English-language publications that specifically examined the interaction between Male Reproductive System and novel PTMs, including “S-nitrosylation”, “crotonylation”, “2-hydroxyisobutyrylation”, “lactylation”, “polysialylation”, “myristoylation” and “SUMOylation”, including both original research and review articles. This review did not involve formal statistical analysis or meta-analytic techniques.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195132"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MOV10-mediated alternative splicing regulates mesangial cell proliferation in diabetic kidney disease","authors":"Qijia Wang ,&nbsp;Xinyu Chong ,&nbsp;Handeng Liu ,&nbsp;Rui Peng ,&nbsp;Xuemei Peng ,&nbsp;Xiaohui Liao ,&nbsp;Yan Sun ,&nbsp;Zheng Zhang","doi":"10.1016/j.bbagrm.2026.195138","DOIUrl":"10.1016/j.bbagrm.2026.195138","url":null,"abstract":"<div><h3>Background</h3><div>Diabetic kidney disease (DKD) is a major microvascular complication of diabetes, characterized by abnormal mesangial cell (MC) proliferation, yet the underlying mechanisms remain unclear.</div></div><div><h3>Methods</h3><div>Using RNA-seq and qRT-PCR, Mov10 was identified as the most highly expressed splicing factor (SF) in high-glucose MCs among seven candidates (Mov10, Ssb, Rbm25, Fastk, Dek, Nsrp1, Cwc15). Functional assays (EdU, CCK-8) assessed MC proliferation, while qRT-PCR and Western blot measured inflammatory and fibrotic markers. RIP-seq, RNA-seq, and bioinformatics analyses were used to identify MOV10-binding sites, target genes, pathways, and alternative splicing (AS) events.</div></div><div><h3>Results</h3><div>Transcriptome analysis revealed extensive AS in DKD, with exon skipping being the most frequent. MOV10 knockdown suppressed MC proliferation and reduced inflammation and fibrosis, whereas MOV10 overexpression had opposite effects. RIP-seq showed MOV10 preferentially bound the ACGACG motif within CDS regions. MOV10 regulated AS of proliferation-related genes, including <em>Tead1</em>, <em>Dcbld2</em>, <em>Slc9a5</em>, <em>Akap13</em>, <em>Tfdp2</em>, and <em>Trp53bp1</em>, primarily via exon skipping.</div></div><div><h3>Conclusions</h3><div>This study identifies MOV10 as a novel DKD-associated splicing factor. By modulating AS of proliferation-related genes, MOV10 promotes mesangial proliferation, inflammation, and fibrosis, highlighting a potential therapeutic target in DKD.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195138"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146121221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-149-3p–mediated TIMP3 restoration suppresses tumor aggressiveness in sorafenib-resistant liver cancer cell","authors":"Sanghee Park ,&nbsp;Taehyun Park ,&nbsp;Dayoung Choi ,&nbsp;Soeun Kim ,&nbsp;Hyunjung Cho ,&nbsp;Misu Lee","doi":"10.1016/j.bbagrm.2026.195136","DOIUrl":"10.1016/j.bbagrm.2026.195136","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a highly lethal malignancy in which acquired resistance to sorafenib remains a major therapeutic challenge. To investigate mechanisms of resistance, we performed transcriptomic profiling of sorafenib-resistant HCC cells, which revealed enrichment of processes related to tumor progression, including mitotic regulation, chromatin remodeling, and apoptotic signaling. Notably, these cells displayed marked downregulation of tissue inhibitor of metalloproteinases-3 (TIMP3), a tumor suppressor known to regulate invasion and epithelial–mesenchymal transition (EMT). Functional studies showed that TIMP3 overexpression (OV) suppressed cell viability, stemness-associated proteins, and a key cell cycle regulator, while upregulating apoptosis-related proteins. Conversely, TIMP3 knockdown (KD) enhanced proliferation, stemness, and EMT. EMT markers were reduced in TIMP3-OV cells but increased with TIMP3-KD, consistent with spheroid sprouting assays, highlighting TIMP3 as a brake on aggressiveness. To explore upstream regulators, we integrated in silico predictions with validation, identifying miR-149-3p as a novel repressor of TIMP3. miR-149-3p overexpression reduced TIMP3 levels and promoted EMT and invasion, whereas inhibition of miR-149-3p restored TIMP3 expression and suppressed migration. Clinical analyses using TCGA datasets and HCC tissue microarrays confirmed significantly lower TIMP3 expression in tumors compared with normal liver tissue, and showed inverse correlations between TIMP3 and proliferative or stemness markers, including Ki67 and CD44. Collectively, these findings establish a mechanistic axis in which miR-149-3p–mediated suppression of TIMP3 promotes sorafenib resistance, EMT, and stemness in HCC. This work identifies TIMP3 as a pivotal determinant of tumor aggressiveness and suggests restoring TIMP3 or targeting downstream pathways as strategies to overcome resistance.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195136"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tet2-mediated Pref-1 activation delays adipocyte differentiation","authors":"Brigitta Veda Devani ,&nbsp;Hye Su Moon ,&nbsp;Ana Braza ,&nbsp;Timoty Ekaputra ,&nbsp;Audrey Christine ,&nbsp;Jae Won Shim ,&nbsp;Su Jung Song","doi":"10.1016/j.bbagrm.2026.195137","DOIUrl":"10.1016/j.bbagrm.2026.195137","url":null,"abstract":"<div><div>Ten-eleven translocation 2 (Tet2) catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine, facilitating active DNA demethylation. Although implicated in adipogenesis, its precise role remains controversial. Here, we investigated Tet2 function during early 3T3-L1 adipocyte differentiation, focusing on regulation of the imprinted gene <em>Pref-1</em>. Differentiation time-course experiments revealed that Tet2 protein, but not mRNA, was progressively reduced via proteasome-dependent degradation, contrasting with previous reports of <em>Tet2</em> mRNA upregulation. Tet2 overexpression delayed lipid accumulation and reduced adipogenic marker expression, whereas knockdown had the opposite effect. Mechanistically, Tet2 positively regulated Pref-1 transcription by demethylating specific differentially methylated regions in its promoter and exon 6. Loss of Tet2 increased DNA methylation and decreased hydroxymethylation at these loci, leading to Pref-1 repression and derepression of C/EBPα and PPARγ. This stage-specific, proteasome-mediated downregulation of Tet2 integrates epigenetic and post-translational control to regulate adipocyte commitment. The Tet2–Pref-1 axis offers mechanistic insight into adipose tissue expansion and may represent a therapeutic target for obesity and imprinting-related disorders.</div></div>","PeriodicalId":55382,"journal":{"name":"Biochimica et Biophysica Acta-Gene Regulatory Mechanisms","volume":"1869 1","pages":"Article 195137"},"PeriodicalIF":3.1,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}