Clinical Epigenetics最新文献

{"title":"TEC-mediated tRF-31R9J regulates histone lactylation and acetylation by HDAC1 to suppress hepatocyte ferroptosis and improve non-alcoholic steatohepatitis.","authors":"Juanjuan Zhu, Xian Wu, Mao Mu, Quan Zhang, Xueke Zhao","doi":"10.1186/s13148-025-01813-3","DOIUrl":"10.1186/s13148-025-01813-3","url":null,"abstract":"<p><strong>Background: </strong>Tectorigenin (TEC) is a monomer of anthocyanin, which we found exhibits hepatoprotective effects. tRNA-derived fragments (tRFs) and ferroptosis play important roles in the pathogenesis of non-alcoholic steatohepatitis (NASH). Recent discoveries have revealed that histone lactylation and acetylation play a crucial role in connecting cellular metabolism and epigenetic regulation through post-translational modification of histones. However, it is unclear whether TEC improves NASH by regulating histone lactylation, acetylation and hepatocyte ferroptosis through tRFs.</p><p><strong>Results: </strong>In this study, we demonstrated that TEC significantly inhibits free fatty acids-induced hepatocyte ferroptosis both in vitro and in vivo. We identified tRF-31R9J (tRF-31-R9JP9P9NH5HYD) involved in TEC regulation of ferroptosis in steatosis hepatocytes. Overexpression of tRF-31R9J suppressed hepatocyte ferroptosis and enhanced cell viability in steatosis HepG2 cells. Knockdown of tRF-31R9J partially counteracted the inhibitory effect of TEC on ferroptosis in hepatocytes. Mechanistically, tRF-31R9J recruited HDAC1 to reduce the levels of histone lactylation and acetylation modifications of the pro-ferroptosis genes ATF3, ATF4, and CHAC1, thereby inhibiting their gene expression.</p><p><strong>Conclusions: </strong>This study demonstrates that TEC-mediated tRF-31R9J inhibits hepatocyte ferroptosis through HDAC1-regulated histone delactylation and deacetylation, thereby improving NASH. These discoveries offer a theoretical foundation and new strategies for the medical management of NASH.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"9"},"PeriodicalIF":4.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines.","authors":"Sam Humphries, Sean M Burnard, Courtney D Eggins, Simon Keely, Danielle R Bond, Heather J Lee","doi":"10.1186/s13148-025-01812-4","DOIUrl":"10.1186/s13148-025-01812-4","url":null,"abstract":"<p><strong>Background: </strong>Hypomethylating agents (HMA), such as azacytidine (AZA) and decitabine (DAC), are epigenetic therapies used to treat some patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome. HMAs act in a replication-dependent manner to remove DNA methylation from the genome. However, AML cells targeted by HMA therapy are often quiescent within the bone marrow, where oxygen levels are low. In this study, we investigate the effects of hypoxia on HMA responses in AML cells.</p><p><strong>Results: </strong>AML cell lines (MOLM-13, MV-4-11, HL-60) were treated with DAC (100 nM) or AZA (500-2000 nM) in normoxic (21% O₂) and hypoxic (1% O₂) conditions. Hypoxia significantly reduced AML cell growth across all cell lines, with no additional effects observed upon HMA treatment. Hypoxia had no impact on the extent of DNA hypomethylation induced by DAC treatment, but limited AZA-induced loss of methylation from the genome. Transcriptional responses to HMA treatment were also altered, with HMAs failing to up-regulate antigen presentation pathways in hypoxia. In particular, cell surface expression of the MHC class II receptor, HLA-DR, was increased by DAC treatment in normoxia, but not hypoxia.</p><p><strong>Conclusion: </strong>Our results suggest that HMA-induced antigen presentation may be impaired by hypoxia. This study highlights the need to consider microenvironmental factors when designing co-treatment strategies to improve HMA therapeutic efficacy.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"8"},"PeriodicalIF":4.8,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001356","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic age acceleration and methylation differences in IgG4-related cholangitis and primary sclerosing cholangitis.","authors":"Alexandra Noble, Rodrigo Motta, Silvia Cabras, Belen Moron Flores, Jan Nowak, Aleksandra Glapa-Nowak, Alessandra Geremia, Jack Satsangi, Emma Culver","doi":"10.1186/s13148-024-01803-x","DOIUrl":"10.1186/s13148-024-01803-x","url":null,"abstract":"<p><strong>Background: </strong>IgG4-related cholangitis (IgG4-SC) and primary sclerosing cholangitis (PSC) are chronic fibro-inflammatory hepatobiliary conditions, with genetic, environmental, and immunologic risk factors, in which epigenetic alterations may provide insights into pathophysiology and novel biomarkers. This study is the first to assess methylation signatures in IgG4-SC.</p><p><strong>Results: </strong>Whole blood DNA methylation profiling and genotyping was performed in 264 individuals; 47 with IgG4-SC, 65 with PSC, 64 with ulcerative colitis (UC), and 88 healthy controls. We identified 19 significant methylation differences between IgG4-SC and controls and 38 between PSC and controls. IgG4-SC and PSC shared 8 probes. Inflammatory genes (including CEP97, IFNAR1, TXK, HERC6, C5orf36, PYY, and MTRNR2L1) were predominantly involved in dysregulated methylation. Epigenetic age acceleration was observed in patients with IgG4-SC, but not in those with PSC or UC. meQTL analyses to identify genetic determinants of methylation revealed a strong human leucocyte antigen (HLA) signal in both PSC and IgG4-SC (HLA-DQB2, HLA-DPA1, HLA-F and HLA-DRA).</p><p><strong>Conclusions: </strong>We identify novel epigenetic alterations in IgG4-SC and PSC, with biological age acceleration in IgG4-SC, providing insights into disease pathogenesis, and highlight the role of genetic variation especially within the HLA region in shaping the methylome.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"6"},"PeriodicalIF":4.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"How do lifestyle and environmental factors influence the sperm epigenome? Effects on sperm fertilising ability, embryo development, and offspring health.","authors":"Ayazhan Akhatova, Celine Jones, Kevin Coward, Marc Yeste","doi":"10.1186/s13148-025-01815-1","DOIUrl":"10.1186/s13148-025-01815-1","url":null,"abstract":"<p><p>Recent studies support the influence of paternal lifestyle and diet before conception on the health of the offspring via epigenetic inheritance through sperm DNA methylation, histone modification, and small non-coding RNA (sncRNA) expression and regulation. Smoking may induce DNA hypermethylation in genes related to anti-oxidation and insulin resistance. Paternal diet and obesity are associated with greater risks of metabolic dysfunction in offspring via epigenetic alterations in the sperm. Metabolic changes, such as high blood glucose levels and increased body weight, are commonly observed in the offspring of fathers subjected to chronic stress, in addition to an enhanced risk of depressive-like behaviour and increased sensitivity to stress in both the F0 and F1 generations. DNA methylation is correlated with alterations in sperm quality and the ability to fertilise oocytes, possibly via a differentially regulated MAKP81IP3 signalling pathway. Paternal exposure to toxic endocrine-disrupting chemicals (EDCs) is also linked to the transgenerational transmission of increased predisposition to disease, infertility, testicular disorders, obesity, and polycystic ovarian syndrome (PCOS) in females through epigenetic changes during gametogenesis. As the success of assisted reproductive technology (ART) is also affected by paternal diet, BMI, and alcohol consumption, its outcomes could be improved by modifying factors that are dependent on male lifestyle choices and environmental factors. This review discusses the importance of epigenetic signatures in sperm-including DNA methylation, histone retention, and sncRNA-for sperm functionality, early embryo development, and offspring health. We also discuss the mechanisms by which paternal lifestyle and environmental factors (obesity, smoking, EDCs, and stress) may impact the sperm epigenome.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"7"},"PeriodicalIF":4.8,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740528/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature.","authors":"Jan Fischer, Mariëlle Alders, Marcel M A M Mannens, David Genevieve, Karl Hackmann, Evelin Schröck, Bekim Sadikovic, Joseph Porrmann","doi":"10.1186/s13148-024-01807-7","DOIUrl":"10.1186/s13148-024-01807-7","url":null,"abstract":"<p><p>Autosomal dominant CDK13-related disease is characterized by congenital heart defects, dysmorphic facial features, and intellectual developmental disorder (CHDFIDD). Heterozygous pathogenic variants, particularly missense variants in the kinase domain, have previously been described as disease causing. Using the determination of a methylation pattern and comparison with an established episignature, we reveal the first hypomorphic variant in the kinase domain of CDK13, leading to a never before described autosomal recessive form of CHDFIDD in a boy with characteristic features. This highlights the utility of episignatures in variant interpretation, as well as a potential novel diagnostic approach in unsolved cases or for disease prognosis.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"5"},"PeriodicalIF":4.8,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic regulation and post-translational modifications of ferroptosis-related factors in cardiovascular diseases.","authors":"Chunlu Jing, Yupeng Wu, Yuzhu Zhang, Zaihan Zhu, Yong Zhang, Zhen Liu, Dandan Sun","doi":"10.1186/s13148-024-01809-5","DOIUrl":"10.1186/s13148-024-01809-5","url":null,"abstract":"<p><p>As an important element of the human body, iron participates in numerous physiological and biochemical reactions. In the past decade, ferroptosis (a form of iron-dependent regulated cell death) has been reported to contribute to the pathogenesis and progression of various diseases. The stability of iron in cardiomyocytes is crucial for the maintenance of normal physiological cardiac activity. Ferroptosis has been detected in many cardiovascular diseases (CVDs), including coronary heart disease, myocardial ischemia-reperfusion injury, heart failure, and chemotherapy-induced myocardial damage. In cardiomyocytes, epigenetic regulation and post-translational modifications regulate the expression of ferroptosis-related factors, maintain iron homeostasis, and participate in the progression of CVDs. Currently, there is no detailed mechanism to explain the relationship between epigenetic regulation and ferroptosis in CVDs. In this review, we provide an initial summary of the core mechanisms of ferroptosis in cardiomyocytes, with first focus on the epigenetic regulation and expression of ferroptosis-related factors in the context of common cardiovascular diseases. We anticipate that the new insights into the pathogenesis of CVDs provided here will inspire the development of clinical interventions to specifically target the active sites of these factors, reducing the harmfulness of ferroptosis to human health.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"4"},"PeriodicalIF":4.8,"publicationDate":"2025-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11724467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A meta-analysis of epigenome-wide association studies of ultra-processed food consumption with DNA methylation in European children.","authors":"Joana Llauradó-Pont, Nikos Stratakis, Giovanni Fiorito, Evangelos Handakas, Alexander Neumann, Henrique Barros, Anne Lise Brantsæter, Kiara Chang, Leda Chatzi, Janine F Felix, Regina Grazuleviciene, Vincent W V Jaddoe, Marianna Karachaliou, Marion Lecorguillé, Carla Lopes, Christopher Millett, Rosemary R C McEachan, Eleni Papadopoulou, Remy Slama, Eszter P Vamos, Paolo Vineis, Martine Vrijheid, John Wright, Trudy Voortman, Mariona Bustamante, Oliver Robinson, Camille Lassale","doi":"10.1186/s13148-024-01782-z","DOIUrl":"https://doi.org/10.1186/s13148-024-01782-z","url":null,"abstract":"<p><strong>Background/objective: </strong>There is limited knowledge on how diet affects the epigenome of children. Ultra-processed food (UPF) consumption is emerging as an important factor impacting health, but mechanisms need to be uncovered. We therefore aimed to assess the association between UPF consumption and DNA methylation in children.</p><p><strong>Methods: </strong>We conducted a meta-analysis of epigenome-wide association studies (EWAS) from a total of 3152 children aged 5-11 years from four European studies (HELIX, Generation XXI, ALSPAC, and Generation R). UPF consumption was defined applying the Nova food classification system (group 4), and DNA methylation was measured in blood with Illumina Infinium Methylation arrays. Associations were estimated within each cohort using robust linear regression models, adjusting for relevant covariates, followed by a meta-analysis of the resulting EWAS estimates.</p><p><strong>Results: </strong>Although no CpG was significant at FDR level, we found suggestive associations (p-value < 10^-5) between UPF consumption and methylation at seven CpG sites. Three of them, cg00339913 (PHYHIP), cg03041696 (intergenic), and cg03999434 (intergenic), were negatively associated, whereas the other four, cg14665028 (NHEJ1), cg18968409 (intergenic), cg24730307 (intergenic), and cg09709951 (ATF7), were positively associated with UPF intake. These CpGs have been previously associated with health outcomes such as carcinomas, and the related genes are mainly involved in pathways related to thyroid hormones and liver function.</p><p><strong>Conclusion: </strong>We only found suggestive changes in methylation at 7 CpGs associated with UPF intake in a large EWAS among children: although this shows a potential impact of UPF intake on DNAm, this might not be a key mechanism underlying the health effects of UPFs in children. There is a need for more detailed dietary assessment in children studies and of intervention studies to assess potential epigenetic changes linked to a reduction in UPF in the diet.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"3"},"PeriodicalIF":4.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11706074/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impaired ARID1A expression attenuated the immune response in gastric cancer via histone acetylation.","authors":"Yu Tang, Ruizhi Zhang, Gan Mao, Chong Li, Yisong Gao, Xuebing Zhou, Wenxiang Nie, Tianyu Song, Suao Liu, Kaixiong Tao, Peng Zhang, Wei Li","doi":"10.1186/s13148-024-01805-9","DOIUrl":"10.1186/s13148-024-01805-9","url":null,"abstract":"<p><strong>Background: </strong>The primary objective of this study was to examine whether ARID1A mutations confer a fitness advantage to gastric cancer from an immunological perspective, along with elucidating the underlying mechanism. Additionally, we aimed to identify the clinical potential of combining epigenetic inhibitors with immune checkpoint inhibitors to improve the efficacy of immunotherapy for gastric cancer.</p><p><strong>Methods: </strong>The correlation between ARID1A gene expression and gastric cancer patient survival was analyzed using the GEO dataset GSE62254. The association between chemokines (CXCL9, CXCL10) and ARID1A was conducted using GSE15460 dataset. Real-time PCR was employed for gene expression analysis, while chromatin immunoprecipitation was used to identify transcriptional regulation on target genes. Protein expression and regulation were assessed through various techniques, including Western blot, ELISA, immunohistochemistry, and immunofluorescence. Chromatin DNA accessibility was determined through MNase digestions, transmission electron microscopy, and ChIP-seq. The impact of ARID1A expression and epigenetic inhibitors on tumor immunity in mice was assessed using flow cytometry.</p><p><strong>Results: </strong>ARID1A expression demonstrated a positive correlation with CD8⁺ T cell infiltration and clinical prognosis. The loss of ARID1A expression led to impaired Th1-type chemokines. Additionally, ARID1A depletion was associated with enhanced tumor growth and the absence of CD8⁺ T cells within the tumor microenvironment. The study revealed that ARID1A played a role in promoting histone acetylation and facilitating chromatin accessibility. Notably, the application of deacetylase inhibitors effectively reversed the effects of ARID1A depletion on tumor progression and significantly enhanced the efficacy of immunotherapy.</p><p><strong>Conclusion: </strong>Gastric cancer with ARID1A mutations modulates immune cell chemotaxis within the tumor microenvironment by influencing histone acetylation. Deacetylase inhibitors have the potential to alter the secretion of chemokines for tumor immune cells, consequently enhancing the effectiveness of immune checkpoint inhibitor therapy in ARID1A-mutated gastric cancer.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"2"},"PeriodicalIF":4.8,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the causal impact of smoking and its DNA methylation signatures on cardiovascular disease: Mendelian randomization and colocalization analysis.","authors":"Si Cao, Youjie Zeng, Ke Pang, Minghua Chen, Ren Guo, Nayiyuan Wu, Chao Fang, Huiyin Deng, Xiaoyi Zhang, Xiaohui Xie, Wen Ouyang, Heng Yang","doi":"10.1186/s13148-024-01808-6","DOIUrl":"10.1186/s13148-024-01808-6","url":null,"abstract":"<p><strong>Background: </strong>To explore the mechanisms linking smoking to cardiovascular diseases (CVDs) from an epigenetic perspective.</p><p><strong>Methods: </strong>Mendelian Randomization (MR) analysis was performed to assess the causal effects of smoking behavior and DNA methylation levels at smoking-related CpG sites on nine CVDs, including aortic aneurysm, atrial fibrillation, coronary atherosclerosis, coronary heart disease, heart failure, intracerebral hemorrhage, ischemic stroke, myocardial infarction, subarachnoid hemorrhage. Colocalization analysis was used to further identify key smoking-related CpG sites from the MR causal estimates. Reactome enrichment analysis was used to elucidate the potential mechanisms.</p><p><strong>Results: </strong>MR analysis indicates that smoking behaviors are significantly associated with an increased risk of nine CVDs (OR > 1, P < 0.05). Through MR and colocalization analysis, five key smoking-related CpG sites were ultimately determined. DNA methylation alteration at cg25313468 (located in the TSS1500 region of REST) is simultaneously associated with the risk of atrial fibrillation, coronary atherosclerosis, coronary heart disease, and myocardial infarction. Additionally, cg21647257 (located in the TSS200 region of CLIP3) is associated with the risk of atrial fibrillation; cg06197751 (located in SGEF gene body) and cg07520810 (located in ARID5B gene body) are associated with the risk of coronary atherosclerosis; cg16822035 (located in MCF2L gene body) is associated with the risk of myocardial infarction. Enrichment analysis suggests that phosphatase and tensin homologue (PTEN) may be involved in the downstream mechanisms of cg25313468 (REST).</p><p><strong>Conclusion: </strong>This study uncovers the relationship between smoking, DNA methylation, and CVDs, providing new insights into the pathogenic effect of smoking on CVDs from an epigenetic perspective.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"17 1","pages":"1"},"PeriodicalIF":4.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered chromatin landscape and 3D interactions associated with primary constitutional MLH1 epimutations.","authors":"Paula Climent-Cantó, Marc Subirana-Granés, Mireia Ramos-Rodríguez, Estela Dámaso, Fátima Marín, Covadonga Vara, Beatriz Pérez-González, Helena Raurell, Elisabet Munté, José Luis Soto, Ángel Alonso, GiWon Shin, Hanlee Ji, Megan Hitchins, Gabriel Capellá, Lorenzo Pasquali, Marta Pineda","doi":"10.1186/s13148-024-01770-3","DOIUrl":"10.1186/s13148-024-01770-3","url":null,"abstract":"<p><strong>Background: </strong>Lynch syndrome (LS), characterised by an increased risk for cancer, is mainly caused by germline pathogenic variants affecting a mismatch repair gene (MLH1, MSH2, MSH6, PMS2). Occasionally, LS may be caused by constitutional MLH1 epimutation (CME) characterised by soma-wide methylation of one allele of the MLH1 promoter. Most of these are \"primary\" epimutations, arising de novo without any apparent underlying cis-genetic cause, and are reversible between generations. We aimed to characterise genetic and gene regulatory changes associated with primary CME to elucidate possible underlying molecular mechanisms.</p><p><strong>Methods: </strong>Four carriers of a primary CME and three non-methylated relatives carrying the same genetic haplotype were included. Genetic alterations were sought using linked-read WGS in blood DNA. Transcriptome (RNA-seq), chromatin landscape (ATAC-seq, H3K27ac CUT&Tag) and 3D chromatin interactions (UMI-4C) were studied in lymphoblastoid cell lines. The MLH1 promoter SNP (c.-93G > A, rs1800734) was used as a reporter in heterozygotes to assess allele-specific chromatin conformation states.</p><p><strong>Results: </strong>MLH1 epimutant alleles presented a closed chromatin conformation and decreased levels of H3K27ac, as compared to the unmethylated allele. Moreover, the epimutant MLH1 promoter exhibited differential 3D chromatin contacts, including lost and gained interactions with distal regulatory elements. Of note, rare genetic alterations potentially affecting transcription factor binding sites were found in the promoter-contacting region of CME carriers.</p><p><strong>Conclusions: </strong>Primary CMEs present allele-specific differential interaction patterns with neighbouring genes and regulatory elements. The role of the identified cis-regulatory regions in the molecular mechanism underlying the origin and maintenance of CME requires further investigation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":"16 1","pages":"193"},"PeriodicalIF":4.8,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11686911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}