{"title":"MIMOSA: a resource consisting of improved methylome prediction models increases power to identify DNA methylation-phenotype associations.","authors":"Hunter J Melton, Zichen Zhang, Hong-Wen Deng, Lang Wu, Chong Wu","doi":"10.1080/15592294.2024.2370542","DOIUrl":"10.1080/15592294.2024.2370542","url":null,"abstract":"<p><p>Although DNA methylation (DNAm) has been implicated in the pathogenesis of numerous complex diseases, from cancer to cardiovascular disease to autoimmune disease, the exact methylation sites that play key roles in these processes remain elusive. One strategy to identify putative causal CpG sites and enhance disease etiology understanding is to conduct methylome-wide association studies (MWASs), in which predicted DNA methylation that is associated with complex diseases can be identified. However, current MWAS models are primarily trained using the data from single studies, thereby limiting the methylation prediction accuracy and the power of subsequent association studies. Here, we introduce a new resource, MWAS Imputing Methylome Obliging Summary-level mQTLs and Associated LD matrices (MIMOSA), a set of models that substantially improve the prediction accuracy of DNA methylation and subsequent MWAS power through the use of a large summary-level mQTL dataset provided by the Genetics of DNA Methylation Consortium (GoDMC). Through the analyses of GWAS (genome-wide association study) summary statistics for 28 complex traits and diseases, we demonstrate that MIMOSA considerably increases the accuracy of DNA methylation prediction in whole blood, crafts fruitful prediction models for low heritability CpG sites, and determines markedly more CpG site-phenotype associations than preceding methods. Finally, we use MIMOSA to conduct a case study on high cholesterol, pinpointing 146 putatively causal CpG sites.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2370542"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11225927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141534029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-07-23DOI: 10.1080/15592294.2024.2381856
Adrián López-Catalina, Antonio Reverter, Pamela A Alexandre, Loan T Nguyen, Oscar González-Recio
{"title":"Stress-induced epigenetic effects driven by maternal lactation in dairy cattle: a comethylation network approach.","authors":"Adrián López-Catalina, Antonio Reverter, Pamela A Alexandre, Loan T Nguyen, Oscar González-Recio","doi":"10.1080/15592294.2024.2381856","DOIUrl":"10.1080/15592294.2024.2381856","url":null,"abstract":"<p><p>Epigenetic marks do not follow the Mendelian laws of inheritance. The environment can alter the epigenotype of an individual when exposed to different external stressors. In lactating cows, the first stages of gestation overlap with the lactation peak, creating a negative energy balance that is difficult to overcome with diet. This negative energy balance could affect early embryo development that must compete with the mammary tissue for nutrients. We hypothesize that the methylation profiles of calves born to nonlactating heifers are different from those of calves born to lactating cows. We found 50,277 differentially methylated cytosines and 2,281 differentially methylated regions between these two groups of animals. A comethylation network was constructed to study the correlation between the phenotypes of the mothers and the epigenome of the calves, revealing 265 regions associated with the phenotypes. Our study revealed the presence of DMCs and DMRs in calves gestated by heifers and lactating cows, which were linked to the dam's lactation and the calves' ICAP and milk EBV. Gene-specific analysis highlighted associations with vasculature and organ morphogenesis and cell communication and signalling. These finding support the hypothesis that calves gestated by nonlactating mothers have a different methylation profile than those gestated by lactating cows.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2381856"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271077/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141751406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-03-03DOI: 10.1080/15592294.2024.2323907
Lauren A Opsasnick, Wei Zhao, Lauren L Schmitz, Scott M Ratliff, Jessica D Faul, Xiang Zhou, Belinda L Needham, Jennifer A Smith
{"title":"Epigenome-wide association study of long-term psychosocial stress in older adults.","authors":"Lauren A Opsasnick, Wei Zhao, Lauren L Schmitz, Scott M Ratliff, Jessica D Faul, Xiang Zhou, Belinda L Needham, Jennifer A Smith","doi":"10.1080/15592294.2024.2323907","DOIUrl":"10.1080/15592294.2024.2323907","url":null,"abstract":"<p><p>Long-term psychosocial stress is strongly associated with negative physical and mental health outcomes, as well as adverse health behaviours; however, little is known about the role that stress plays on the epigenome. One proposed mechanism by which stress affects DNA methylation is through health behaviours. We conducted an epigenome-wide association study (EWAS) of cumulative psychosocial stress (<i>n</i> = 2,689) from the Health and Retirement Study (mean age = 70.4 years), assessing DNA methylation (Illumina Infinium HumanMethylationEPIC Beadchip) at 789,656 CpG sites. For identified CpG sites, we conducted a formal mediation analysis to examine whether smoking, alcohol use, physical activity, and body mass index (BMI) mediate the relationship between stress and DNA methylation. Nine CpG sites were associated with psychosocial stress (all <i>p</i> < 9E-07; FDR q < 0.10). Additionally, health behaviours and/or BMI mediated 9.4% to 21.8% of the relationship between stress and methylation at eight of the nine CpGs. Several of the identified CpGs were in or near genes associated with cardiometabolic traits, psychosocial disorders, inflammation, and smoking. These findings support our hypothesis that psychosocial stress is associated with DNA methylation across the epigenome. Furthermore, specific health behaviours mediate only a modest percentage of this relationship, providing evidence that other mechanisms may link stress and DNA methylation.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2323907"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10913704/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-03-03DOI: 10.1080/15592294.2024.2323751
Ji Ren, Xiuying Chen, Jing Li, Yuxin Zan, Shan Wang, Yujie Tan, Yan Ding
{"title":"TET1 inhibits the migration and invasion of cervical cancer cells by regulating autophagy.","authors":"Ji Ren, Xiuying Chen, Jing Li, Yuxin Zan, Shan Wang, Yujie Tan, Yan Ding","doi":"10.1080/15592294.2024.2323751","DOIUrl":"10.1080/15592294.2024.2323751","url":null,"abstract":"<p><p>Methylation modifications play pertinent roles in regulating gene expression and various biological processes. The silencing of the demethylase enzyme TET1 can affect the expressions of key oncogenes or tumour suppressor genes, thus contributing to tumour formation. Nonetheless, how TET1 affects the progression of cervical cancer is yet to be elucidated. In this study, we found that the expression of TET1 was significantly downregulated in cervical cancer tissues. Functionally, TET1 knockdown in cervical cancer cells can promote cell proliferation, migration, invasion, cervical xenograft tumour formation and EMT. On the contrary, its overexpression can reverse the aforementioned processes. Moreover, the autophagy level of cervical cancer cells can be enhanced after TET1 knockdown. Mechanistically, methylated DNA immunoprecipitation (MeDIP)-sequencing and MeDIP quantitative real-time PCR revealed that TET1 mediates the methylation of autophagy promoter regions. These findings suggest that TET1 affects the autophagy of cervical cancer cells by altering the methylation levels of NKRF or HIST1H2AK, but the specific mechanism needs to be investigated further.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2323751"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10913696/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021233","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2023-12-28DOI: 10.1080/15592294.2023.2296275
Guilherme Jeremias, Ana-Belén Muñiz-González, Fernando José Mendes Gonçalves, José-Luis Martínez-Guitarte, Jana Asselman, Joana Luísa Pereira
{"title":"History of exposure to copper influences transgenerational gene expression responses in <i>Daphnia magna</i>.","authors":"Guilherme Jeremias, Ana-Belén Muñiz-González, Fernando José Mendes Gonçalves, José-Luis Martínez-Guitarte, Jana Asselman, Joana Luísa Pereira","doi":"10.1080/15592294.2023.2296275","DOIUrl":"10.1080/15592294.2023.2296275","url":null,"abstract":"<p><p>The establishment of transgenerational effects following chemical exposure is a powerful phenomenon, capable of modulating ecosystem health beyond exposure periods. This study assessed the transgenerational effects occurring due to copper exposure in the invertebrate <i>D. magna</i> at the transcriptional level, while evaluating the role of exposure history on such responses. Thus, daphnids acclimated for several generations in a copper vs. clean medium were then exposed for one generation (F0) to this metal, and monitored for the following non-exposed generations (F1, F2 and F3). Organisms differing in exposure histories showed remarkably different transcriptional profiles at the F0, with naïve organisms being more profoundly affected. These trends were confirmed for F3 treatments, which presented different transcriptional patterns for genes involved in detoxification, oxidative stress, DNA damage repair, circadian clock functioning and epigenetic regulation. Furthermore, regardless of exposure history, a great number of histone modifier genes were always found transcriptionally altered, thus suggesting the involvement of histone modifications in the response of <i>Daphnia</i> to metal exposure. Lastly, remarkably distinct transgenerational transcriptional responses were found between naïve and non-naïve organisms, thereby highlighting the influence of exposure history on gene expression and confirming the capacity of metals to determine transgenerational transcriptional effects across non-exposed generations.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2296275"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761054/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139058236","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-05-08DOI: 10.1080/15592294.2024.2349980
Elizabeth S Nakasone, Tyler J Zemla, Ming Yu, She Yu Lin, Fang-Shu Ou, Kelly Carter, Federico Innocenti, Leonard Saltz, William M Grady, Stacey A Cohen
{"title":"Evaluating the utility of <i>ZNF331</i> promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance).","authors":"Elizabeth S Nakasone, Tyler J Zemla, Ming Yu, She Yu Lin, Fang-Shu Ou, Kelly Carter, Federico Innocenti, Leonard Saltz, William M Grady, Stacey A Cohen","doi":"10.1080/15592294.2024.2349980","DOIUrl":"10.1080/15592294.2024.2349980","url":null,"abstract":"<p><p>While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of <i>ZNF331</i> promoter hypermethylation (m<i>ZNF331</i>) as a prognostic and predictive marker in colon cancer. We examined the association of m<i>ZNF331</i> with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. <i>ZNF331</i> promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of m<i>ZNF331</i> in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. m<i>ZNF331</i> was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with m<i>ZNF331</i> compared to unmethylated <i>ZNF331</i> (unm<i>ZNFF31</i>). There was no significant difference in disease-free or overall survival between patients with m<i>ZNF331</i> versus unm<i>ZNF331</i> colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by <i>ZNF331</i> methylation status. While <i>ZNF331</i> promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of m<i>ZNF331</i> as a prognostic and predictive marker.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2349980"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11085945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-05-26DOI: 10.1080/15592294.2024.2357518
Wanhong He, Haijun Zhu, Sufen Zhang, Guang Shu, Han Lei, Maonan Wang, Gang Yin, Xiaohua Ni, Qihan Wu
{"title":"Epigenetic editing of <i>BRCA1</i> promoter increases cisplatin and olaparib sensitivity of ovarian cancer cells.","authors":"Wanhong He, Haijun Zhu, Sufen Zhang, Guang Shu, Han Lei, Maonan Wang, Gang Yin, Xiaohua Ni, Qihan Wu","doi":"10.1080/15592294.2024.2357518","DOIUrl":"10.1080/15592294.2024.2357518","url":null,"abstract":"<p><p>Drug resistance is the primary contributor to the high mortality rate of ovarian cancer (OC). The loss of <i>BRCA1</i>/2 function is linked to drug sensitivity in OC cells. The aim of this study is to enhance the drug sensitivity of OC cells by inducing <i>BRCA1</i> dysfunction through promoter epigenetic editing. Epigenetic regulatory regions within the <i>BRCA1</i> promoter, affecting gene expression, were initially discerned through analysis of clinical samples. Subsequently, we designed and rigorously validated epigenetic editing tools. Ultimately, we evaluated the cisplatin and olaparib sensitivity of the OC cells after editing. The <i>BRCA1</i> promoter contains two CpG-rich regions, with methylation of the region covering the transcription start site (TSS) strongly correlating with transcription and influencing OC development, prognosis, and homologous recombination (HR) defects. Targeting this region in OC cells using our designed epigenetic editing tools led to substantial and persistent DNA methylation changes, accompanied by significant reductions in H3K27ac histone modifications. This resulted in a notable suppression of <i>BRCA1</i> expression and a decrease in HR repair capacity. Consequently, edited OC cells exhibited heightened sensitivity to cisplatin and olaparib, leading to increased apoptosis rates. Epigenetic inactivation of the <i>BRCA1</i> promoter can enhance cisplatin and olaparib sensitivity of OC cells through a reduction in HR repair capacity, indicating the potential utility of epigenetic editing technology in sensitization therapy for OC.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2357518"},"PeriodicalIF":3.7,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11135871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141154354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-07-14DOI: 10.1080/15592294.2024.2374988
Chunxiao Bu, Zhilong Wang, Xianping Lv, Yanteng Zhao
{"title":"A dual-gene panel of two fragments of methylated IRF4 and one of ZEB2 in plasma cell-free DNA for gastric cancer detection.","authors":"Chunxiao Bu, Zhilong Wang, Xianping Lv, Yanteng Zhao","doi":"10.1080/15592294.2024.2374988","DOIUrl":"10.1080/15592294.2024.2374988","url":null,"abstract":"<p><p>Early detection is crucial for increasing the survival rate of gastric cancer (GC). We aimed to identify a methylated cell-free DNA (cfDNA) marker panel for detecting GC. The differentially methylated CpGs (DMCs) were selected from datasets of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The selected DMCs were validated and further selected in tissue samples (40 gastric cancer and 36 healthy white blood cell samples) and in a quarter sample volume of plasma samples (37 gastric cancer, 12 benign gastric disease, and 43 healthy individuals). The marker combination selected was then evaluated in a normal sample volume of plasma samples (35 gastric cancer, 39 control diseases, and 40 healthy individuals) using real-time methylation-specific PCR (MSP). The analysis of the results compared methods based on 2<sup>-ΔΔCt</sup> values and Ct values. In the results, 30 DMCs were selected through bioinformatics methods, and then 5 were selected for biological validation. The marker combination of two fragments of IRF4 (IRF4-1 and IRF4-2) and one of ZEB2 was selected due to its good performance. The Ct-based method was selected for its good results and practical advantages. The assay, IRF4-1 and IRF4-2 in one fluorescence channel and ZEB2 in another, obtained 74.3% sensitivity for the GC group at any stage, at 92.4% specificity. In conclusion, the panel of IRF4 and ZEB2 in plasma cfDNA demonstrates good diagnostic performance and application potential in clinical settings.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2374988"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11249030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
EpigeneticsPub Date : 2024-12-01Epub Date: 2024-07-06DOI: 10.1080/15592294.2024.2374979
Yee Hoon Foong, Blake Caldwell, Joanne L Thorvaldsen, Christopher Krapp, Clementina A Mesaros, Wanding Zhou, Rahul M Kohli, Marisa S Bartolomei
{"title":"TET1 displays catalytic and non-catalytic functions in the adult mouse cortex.","authors":"Yee Hoon Foong, Blake Caldwell, Joanne L Thorvaldsen, Christopher Krapp, Clementina A Mesaros, Wanding Zhou, Rahul M Kohli, Marisa S Bartolomei","doi":"10.1080/15592294.2024.2374979","DOIUrl":"10.1080/15592294.2024.2374979","url":null,"abstract":"<p><p>TET1/2/3 dioxygenases iteratively demethylate 5-methylcytosine, beginning with the formation of 5-hydroxymethylcytosine (5hmC). The post-mitotic brain maintains higher levels of 5hmC than most peripheral tissues, and TET1 ablation studies have underscored the critical role of TET1 in brain physiology. However, deletion of <i>Tet1</i> precludes the disentangling of the catalytic and non-catalytic functions of TET1. Here, we dissect these functions of TET1 by comparing adult cortex of <i>Tet1</i> wildtype (<i>Tet1</i> WT), a novel <i>Tet1</i> catalytically dead mutant (<i>Tet1</i> HxD), and <i>Tet1</i> knockout (<i>Tet1</i> KO) mice. Using DNA methylation array, we uncover that <i>Tet1</i> HxD and KO mutations perturb the methylation status of distinct subsets of CpG sites. Gene ontology (GO) analysis on specific differential 5hmC regions indicates that TET1's catalytic activity is linked to neuronal-specific functions. RNA-Seq further shows that <i>Tet1</i> mutations predominantly impact the genes that are associated with alternative splicing. Lastly, we performed High-performance Liquid Chromatography Mass-Spectrometry lipidomics on WT and mutant cortices and uncover accumulation of lysophospholipids lysophosphatidylethanolamine and lysophosphatidylcholine in <i>Tet1</i> HxD cortex. In summary, we show that <i>Tet1</i> HxD does not completely phenocopy <i>Tet1</i> KO, providing evidence that TET1 modulates distinct cortical functions through its catalytic and non-catalytic roles.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2374979"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11229741/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141544646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"GGNBP2 regulates histone ubiquitination and methylation in spermatogenesis.","authors":"Kaimin Guo, Yin Cao, Zhiyi Zhao, Jiantao Zhao, Lingyun Liu, Hongliang Wang","doi":"10.1080/15592294.2024.2381849","DOIUrl":"10.1080/15592294.2024.2381849","url":null,"abstract":"<p><p>Gametogenetin binding protein 2 (GGNBP2) was indispensable in normal spermatids for transformation into mature spermatozoa in mice, and when Gametogenetin binding protein 2 is bound to BRCC36 and RAD51, the complex participates in repairing DNA double-strand breaks (DSB) during the meiotic progression of spermatocytes. Ggnbp2 knockout resulted in the up-regulation of H2A<sub>K119ubi</sub> and down-regulation of H2B<sub>K120ubi</sub> in GC-2 cells (mouse spermatogonia-derived cell line) and postnatal day 18 testis lysate. Our results also demonstrated that Gametogenetin binding protein 2 inducedASXL1 to activate the deubiquitinating enzyme BAP1 in deubiquitinating H2A, while Gametogenetin binding protein 2 knockout disrupted the interaction between ASXL1 and BAP1, resulting in BAP1 localization change. Furthermore, the Gametogenetin binding protein 2 deletion reduced H2B ubiquitination by affecting E2 enzymes and E3 ligase binding. Gametogenetin binding protein 2 regulated H2A and H2B ubiquitination levels and controlled H3<sub>K27</sub> and H3<sub>K79</sub> methylation by PRC2 subunits and histone H3K79 methyltransferase. Altogether, our results suggest that Ggnbp2 knockout increased DNA damage response by promoting H2A ubiquitination and H3<sub>K27</sub>trimethylation (H3<sub>K27me3</sub>) and reduced nucleosome stability by decreasing H2B ubiquitination and H3K79 dimethylation (H3<sub>K79me2</sub>), revealing new mechanisms of epigenetic phenomenon during spermatogenesis. Gametogenetin binding protein 2 seems critical in regulating histone modification and chromatin structure in spermatogenesis.</p>","PeriodicalId":11767,"journal":{"name":"Epigenetics","volume":"19 1","pages":"2381849"},"PeriodicalIF":2.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897140","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}