Clinical Epigenetics最新文献

{"title":"DNA methylation markers for oral cancer detection in non- and minimally invasive samples: a systematic review.","authors":"Óscar Rapado-González, Sofia Salta, Rafael López-López, Rui Henrique, María Mercedes Suárez-Cunqueiro, Carmen Jerónimo","doi":"10.1186/s13148-024-01716-9","DOIUrl":"10.1186/s13148-024-01716-9","url":null,"abstract":"<p><p>More than 50% of oral cancer (OC) patients are diagnosed with advanced-stage disease associated with poor prognosis and quality of life, supporting an urgent need to improve early OC detection. The identification of effective molecular markers by minimally invasive approaches has emerged as a promising strategy for OC screening. This systematic review summarizes and evaluates the performance of the DNA methylation markers identified in non- or minimally invasive samples for OC detection. PubMed's MEDLINE, Scopus, Embase, and Cochrane Library databases were systematically searched for studies that evaluated DNA methylation markers in non-invasive and/or minimally invasive samples (oral rinse/saliva, oral brush, and blood) from OC patients. Two investigators independently extracted data on study population characteristics, candidate methylation markers, testing samples, DNA methylation assay, and performance diagnostic outcomes. Methodological study quality was assessed with the Quality Assessment for Studies of Diagnostic Accuracy-2 tool. Thirty-one studies met the inclusion criteria for this systematic review. DNA methylation markers were evaluated in oral rinse/saliva (n = 17), oral brush (n = 9), and blood (n = 7) samples. Methylation-specific PCR (MSP) and quantitative-MSP were the most common DNA methylation assays. Regarding diagnostic performance values for salivary, oral brush, and blood DNA methylation markers, sensitivity and specificity ranged between 3.4-100% and 21-100%, 9-100% and 26.8-100%, 22-70% and 45.45-100%, respectively. Different gene methylation panels showed good diagnostic performance for OC detection. This systematic review discloses the promising value of testing DNA methylation markers in non-invasive (saliva or oral rinse) or minimally invasive (oral brush or blood) samples as a novel strategy for OC detection. However, further validation in large, multicenter, and prospective study cohorts must be carried out to confirm the clinical value of specific DNA methylation markers in this setting.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975248","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":"Epigenome-wide association study on the plasma metabolome suggests self-regulation of the glycine and serine pathway through DNA methylation.","authors":"Jiafei Wu, Victoria Palasantzas, Sergio Andreu-Sánchez, Torsten Plösch, Sam Leonard, Shuang Li, Marc Jan Bonder, Harm-Jan Westra, Joyce van Meurs, Mohsen Ghanbari, Lude Franke, Alexandra Zhernakova, Jingyuan Fu, Joanne A Hoogerland, Daria V Zhernakova","doi":"10.1186/s13148-024-01718-7","DOIUrl":"10.1186/s13148-024-01718-7","url":null,"abstract":"<p><strong>Background: </strong>The plasma metabolome reflects the physiological state of various biological processes and can serve as a proxy for disease risk. Plasma metabolite variation, influenced by genetic and epigenetic mechanisms, can also affect the cellular microenvironment and blood cell epigenetics. The interplay between the plasma metabolome and the blood cell epigenome remains elusive. In this study, we performed an epigenome-wide association study (EWAS) of 1183 plasma metabolites in 693 participants from the LifeLines-DEEP cohort and investigated the causal relationships in DNA methylation-metabolite associations using bidirectional Mendelian randomization and mediation analysis.</p><p><strong>Results: </strong>After rigorously adjusting for potential confounders, including genetics, we identified five robust associations between two plasma metabolites (L-serine and glycine) and three CpG sites located in two independent genomic regions (cg14476101 and cg16246545 in PHGDH and cg02711608 in SLC1A5) at a false discovery rate of less than 0.05. Further analysis revealed a complex bidirectional relationship between plasma glycine/serine levels and DNA methylation. Moreover, we observed a strong mediating role of DNA methylation in the effect of glycine/serine on the expression of their metabolism/transport genes, with the proportion of the mediated effect ranging from 11.8 to 54.3%. This result was also replicated in an independent population-based cohort, the Rotterdam Study. To validate our findings, we conducted in vitro cell studies which confirmed the mediating role of DNA methylation in the regulation of PHGDH gene expression.</p><p><strong>Conclusions: </strong>Our findings reveal a potential feedback mechanism in which glycine and serine regulate gene expression through DNA methylation.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975249","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":"Impact of childhood maltreatment on aging: a comprehensive Mendelian randomization analysis of multiple age-related biomarkers.","authors":"Zheng Zhang, Hao Ren, Rong Han, Qiyin Li, Jiangyou Yu, Yuan Zhao, Liwei Tang, Yadong Peng, Ying Liu, Cheng Gan, Keyi Liu, Qinghua Luo, Haitang Qiu, Chenggang Jiang","doi":"10.1186/s13148-024-01720-z","DOIUrl":"10.1186/s13148-024-01720-z","url":null,"abstract":"<p><strong>Background: </strong>Childhood maltreatment (CM) is linked to long-term adverse health outcomes, including accelerated biological aging and cognitive decline. This study investigates the relationship between CM and various aging biomarkers: telomere length, facial aging, intrinsic epigenetic age acceleration (IEAA), GrimAge, HannumAge, PhenoAge, frailty index, and cognitive performance.</p><p><strong>Methods: </strong>We conducted a Mendelian randomization (MR) study using published GWAS summary statistics. Aging biomarkers included telomere length (qPCR), facial aging (subjective evaluation), and epigenetic age markers (HannumAge, IEAA, GrimAge, PhenoAge). The frailty index was calculated from clinical assessments, and cognitive performance was evaluated with standardized tests. Analyses included Inverse-Variance Weighted (IVW), MR Egger, and Weighted Median (WM) methods, adjusted for multiple comparisons.</p><p><strong>Results: </strong>CM was significantly associated with shorter telomere length (IVW: β = - 0.1, 95% CI - 0.18 to - 0.02, pFDR = 0.032) and increased HannumAge (IVW: β = 1.33, 95% CI 0.36 to 2.3, pFDR = 0.028), GrimAge (IVW: β = 1.19, 95% CI 0.19 to 2.2, pFDR = 0.040), and PhenoAge (IVW: β = 1.4, 95% CI 0.12 to 2.68, pFDR = 0.053). A significant association was also found with the frailty index (IVW: β = 0.31, 95% CI 0.13 to 0.49, pFDR = 0.006). No significant associations were found with facial aging, IEAA, or cognitive performance.</p><p><strong>Conclusions: </strong>CM is linked to accelerated biological aging, shown by shorter telomere length and increased epigenetic aging markers. CM was also associated with increased frailty, highlighting the need for early interventions to mitigate long-term effects. Further research should explore mechanisms and prevention strategies.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299400/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893038","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":"Anti-tumour activity of Panobinostat in oesophageal adenocarcinoma and squamous cell carcinoma cell lines","authors":"Nair Lopes, Sofia Salta, Bianca Troncarelli Flores, Vera Miranda-Gonçalves, Margareta P. Correia, Davide Gigliano, Rita Guimarães, Rui Henrique, Carmen Jerónimo","doi":"10.1186/s13148-024-01700-3","DOIUrl":"https://doi.org/10.1186/s13148-024-01700-3","url":null,"abstract":"Oesophageal cancer remains a challenging disease with high mortality rates and few therapeutic options. In view of these difficulties, epigenetic drugs have emerged as potential alternatives for patient care. The goal of this study was to evaluate the effect and biological consequences of Panobinostat treatment, an HDAC (histone deacetylase) inhibitor already approved for treatment of patients with multiple myeloma, in oesophageal cell lines of normal and malignant origin, with the latter being representative of the two main histological subtypes: adenocarcinoma and squamous cell carcinoma. Panobinostat treatment inhibited growth and hindered proliferation, colony formation and invasion of oesophageal cancer cells. Considering HDAC tissue expression, HDAC1 was significantly upregulated in normal oesophageal epithelium in comparison with tumour tissue, whereas HDAC3 was overexpressed in oesophageal cancer compared to non-malignant mucosa. No differences between normal and tumour tissue were observed for HDAC2 and HDAC8 expression. Panobinostat exposure effectively impaired malignant features of oesophageal cancer cells. Because HDAC3 was shown to be overexpressed in oesophageal tumour samples, this epigenetic drug may represent an alternative therapeutic option for oesophageal cancer patients.","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141887346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A case of an Angelman-syndrome caused by an intragenic duplication of UBE3A uncovered by adaptive nanopore sequencing.","authors":"Laura Holthöfer, Stefan Diederich, Verena Haug, Lioba Lehmann, Charlotte Hewel, Norbert W Paul, Susann Schweiger, Susanne Gerber, Matthias Linke","doi":"10.1186/s13148-024-01711-0","DOIUrl":"10.1186/s13148-024-01711-0","url":null,"abstract":"<p><p>Adaptive nanopore sequencing as a diagnostic method for imprinting disorders and episignature analysis revealed an intragenic duplication of Exon 6 and 7 in UBE3A (NM_000462.5) in a patient with relatively mild Angelman-like syndrome. In an all-in-one nanopore sequencing analysis DNA hypomethylation of the SNURF:TSS-DMR, known contributing deletions on the maternal allele and point mutations in UBE3A could be ruled out as disease drivers. In contrast, breakpoints and orientation of the tandem duplication could clearly be defined. Segregation analysis in the family showed that the duplication derived de novo in the maternal grandfather. Our study shows the benefits of an all-in-one nanopore sequencing approach for the diagnostics of Angelman syndrome and other imprinting disorders.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878464","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":"Multi-locus imprinting disturbance (MLID): interim joint statement for clinical and molecular diagnosis.","authors":"Deborah J G Mackay, Gabriella Gazdagh, David Monk, Frederic Brioude, Eloise Giabicani, Izabela M Krzyzewska, Jennifer M Kalish, Saskia M Maas, Masayo Kagami, Jasmin Beygo, Tiina Kahre, Jair Tenorio-Castano, Laima Ambrozaitytė, Birutė Burnytė, Flavia Cerrato, Justin H Davies, Giovanni Battista Ferrero, Olga Fjodorova, Africa Manero-Azua, Arrate Pereda, Silvia Russo, Pierpaola Tannorella, Karen I Temple, Katrin Õunap, Andrea Riccio, Guiomar Perez de Nanclares, Eamonn R Maher, Pablo Lapunzina, Irène Netchine, Thomas Eggermann, Jet Bliek, Zeynep Tümer","doi":"10.1186/s13148-024-01713-y","DOIUrl":"10.1186/s13148-024-01713-y","url":null,"abstract":"<p><strong>Background: </strong>Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need.</p><p><strong>Methods: </strong>A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations.</p><p><strong>Results: </strong>In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID.</p><p><strong>Conclusions: </strong>MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874302","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":"Retraction Note: The predictive value of BTG1 for the response of newly diagnosed acute myeloid leukemia to decitabine.","authors":"Yi Li, Xia Mao, Mengyuan Li, Li Li, Xiwen Tong, Lifang Huang","doi":"10.1186/s13148-024-01715-w","DOIUrl":"10.1186/s13148-024-01715-w","url":null,"abstract":"","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874303","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":"DNA methylation and whole-genome transcription analysis in CD4⁺ T cells from systemic lupus erythematosus patients with or without renal damage.","authors":"Xiaomin Liu, Siyu Zhou, Mengjie Huang, Ming Zhao, Weiguang Zhang, Qun Liu, Kangkang Song, Xu Wang, Jiaona Liu, Qing OuYang, Zheyi Dong, Ming Yang, Zhenzhen Li, Li Lin, Yi Liu, Yang Yu, Simin Liao, Jian Zhu, Lin Liu, Wenge Li, Linpei Jia, Aihua Zhang, Chaomin Guo, LiuYang Yang, Qing Gang Li, Xueyuan Bai, Ping Li, Guangyan Cai, Qianjin Lu, Xiangmei Chen","doi":"10.1186/s13148-024-01699-7","DOIUrl":"10.1186/s13148-024-01699-7","url":null,"abstract":"<p><strong>Background: </strong>Lupus nephritis (LN) is the most common cause of kidney injury in systemic lupus erythematosus (SLE) patients and is associated with increased mortality. DNA methylation, one of the most important epigenetic modifications, has been reported as a key player in the pathogenesis of SLE. Hence, our article aimed to explore DNA methylation in CD4⁺ T cells from LNs to identify additional potential biomarkers and pathogenic genes involved in the progression of LN.</p><p><strong>Methods: </strong>Our study enrolled 46 SLE patients with or without kidney injury and 23 healthy controls from 2019 to 2022. CD4⁺ T cells were sorted for DNA methylation genotyping and RNA-seq. Through bioinformatics analysis, we identified the significant differentially methylated CpG positions (DMPs) only in the LN group and validated them by Bisulfite PCR. Integration analysis was used to screen for differentially methylated and expressed genes that might be involved in the progression of LN, and the results were analyzed via cell experiments and flow cytometry.</p><p><strong>Results: </strong>We identified 243 hypomethylated sites and 778 hypermethylated sites only in the LN cohort. Three of these DMPs, cg08332381, cg03297029, and cg16797344, were validated by Bisulfite PCR and could be potential biomarkers for LN. Integrated analysis revealed that the expression of BCL2L14 and IFI27 was regulated by DNA methylation, which was validated by azacytidine (5-aza) treatment. The overexpression of BCL2L14 in CD4⁺ T cells might induce renal fibrosis and inflammation by regulating the differentiation and function of Tfh cells.</p><p><strong>Conclusion: </strong>Our study identified novel aberrant DMPs in CD4⁺ T cells only in LN patients and DNA methylation-regulated genes that could be potential LN biomarkers. BCL2L14 is likely involved in the progression of LN and might be a treatment target.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141855020","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":"DNA methylation-mediated suppression of TUSC1 expression regulates the malignant progression of esophagogastric junction cancer.","authors":"Zhiqiang Liu, Ganshu Xia, Xiaolong Liang, Baozhong Li, Jingyu Deng","doi":"10.1186/s13148-024-01689-9","DOIUrl":"10.1186/s13148-024-01689-9","url":null,"abstract":"<p><strong>Background: </strong>Esophagogastric junction cancer (EJC) refers to malignant tumors that develop at the junction between the stomach and the esophagus. TUSC1 is a recently identified tumor suppressor gene known for its involvement in various types of cancer. The objective of this investigation was to elucidate the regulatory influence of DNA methylation on TUSC1 expression and its role in the progression of EJC.</p><p><strong>Methods: </strong>Bioinformatics software was utilized to analyze the expression of TUSC1, enriched pathways, and highly methylated sites in the promoter region. TUSC1 expression in EJC was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot (WB), and immunohistochemistry. Methylation-specific PCR was employed to detect the methylation level of TUSC1. To analyze the effects of TUSC1 and 5-AZA-2 on tumor cell proliferation, migration, invasion, cell cycle, and apoptosis, several assays including CCK-8, colony formation, transwell, and flow cytometry were conducted. The expression of MDM2 was assessed using qRT-PCR and WB. WB detected the expression of p53, and p-p53, markers for EJC cell proliferation, epithelial-mesenchymal transition, and apoptosis. The role of TUSC1 in tumor occurrence in vivo was examined using a xenograft mouse model.</p><p><strong>Results: </strong>TUSC1 expression was significantly downregulated in EJC. Overexpression of TUSC1 and treatment with 5-AZA-2 inhibited the malignant progression of EJC cells. In EJC, low methylation levels promoted the expression of TUSC1. Upregulation of TUSC1 suppressed the expression of MDM2 and activated the p53 signaling pathway. Inactivation of this pathway attenuated the inhibitory effect of TUSC1 overexpression on EJC cell proliferation, migration, invasion, and other behaviors. Animal experiments demonstrated that TUSC1 overexpression inhibited EJC tumor growth and metastasis in vivo.</p><p><strong>Conclusion: </strong>TUSC1 was commonly downregulated in EJC and regulated by methylation. It repressed the malignant progression of EJC tumors by mediating the p53 pathway, suggesting its potential as a diagnostic and therapeutic target for EJC.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11267789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751276","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 and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant.","authors":"Jan Frohlich, Niccolò Liorni, Manuel Mangoni, Gabriela Lochmanová, Pavlína Pírek, Nikola Kaštánková, Pille Pata, Jan Kucera, George N Chaldakov, Anton B Tonchev, Illar Pata, Vera Gorbunova, Eric Leire, Zbyněk Zdráhal, Tommaso Mazza, Manlio Vinciguerra","doi":"10.1186/s13148-024-01710-1","DOIUrl":"10.1186/s13148-024-01710-1","url":null,"abstract":"<p><strong>Background: </strong>Obesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level.</p><p><strong>Methods: </strong>We analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches.</p><p><strong>Results: </strong>Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner.</p><p><strong>Conclusions: </strong>SIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.</p>","PeriodicalId":10366,"journal":{"name":"Clinical Epigenetics","volume":null,"pages":null},"PeriodicalIF":4.8,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11265064/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733699","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}