Epigenetics & Chromatin最新文献

{"title":"Epigene functional diversity: isoform usage, disordered domain content, and variable binding partners.","authors":"Leroy Bondhus, Aileen A Nava, Isabelle S Liu, Valerie A Arboleda","doi":"10.1186/s13072-025-00571-z","DOIUrl":"10.1186/s13072-025-00571-z","url":null,"abstract":"<p><strong>Background: </strong>Epigenes are defined as proteins that perform post-translational modification of histones or DNA, reading of post-translational modifications, form complexes with epigenetic factors or changing the general structure of chromatin. This specialized group of proteins is responsible for controlling the organization of genomic DNA in a cell-type specific fashion, controlling normal development in a spatial and temporal fashion. Moreover, mutations in epigenes have been implicated as causal in germline pediatric disorders and as driver mutations in cancer. Despite their importance to human disease, to date, there has not been a systematic analysis of the sources of functional diversity for epigenes at large. Epigenes' unique functions that require the assembly of pools within the nucleus suggest that their structure and amino acid composition would have been enriched for features that enable efficient assembly of chromatin and DNA for transcription, splicing, and post-translational modifications.</p><p><strong>Results: </strong>In this study, we assess the functional diversity stemming from gene structure, isoforms, protein domains, and multiprotein complex formation that drive the functions of established epigenes. We found that there are specific structural features that enable epigenes to perform their variable roles depending on the cellular and environmental context. First, epigenes are significantly larger and have more exons compared with non-epigenes which contributes to increased isoform diversity. Second epigenes participate in more multimeric complexes than non-epigenes. Thirdly, given their proposed importance in membraneless organelles, we show epigenes are enriched for substantially larger intrinsically disordered regions (IDRs). Additionally, we assessed the specificity of their expression profiles and showed epigenes are more ubiquitously expressed consistent with their enrichment in pediatric syndromes with intellectual disability, multiorgan dysfunction, and developmental delay. Finally, in the L1000 dataset, we identify drugs that can potentially be used to modulate expression of these genes.</p><p><strong>Conclusions: </strong>Here we identify significant differences in isoform usage, disordered domain content, and variable binding partners between human epigenes and non-epigenes using various functional genomics datasets from Ensembl, ENCODE, GTEx, HPO, LINCS L1000, and BrainSpan. Our results contribute new knowledge to the growing field focused on developing targeted therapies for diseases caused by epigene mutations, such as chromatinopathies and cancers.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"8"},"PeriodicalIF":4.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11786378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of relationships between epigenetic age acceleration and multiple sclerosis: a bidirectional mendelian randomization study.","authors":"Hongwei Liu, Hanqing Zhang, Zhaoxu Yin, Miaomiao Hou","doi":"10.1186/s13072-025-00567-9","DOIUrl":"10.1186/s13072-025-00567-9","url":null,"abstract":"<p><strong>Background: </strong>The DNA methylation-based epigenetic clocks are increasingly recognized for their precision in predicting aging and its health implications. Although prior research has identified connections between accelerated epigenetic aging and multiple sclerosis, the chronological and causative aspects of these relationships are yet to be elucidated. Our research seeks to clarify these potential causal links through a bidirectional Mendelian randomization study.</p><p><strong>Methods: </strong>This analysis employed statistics approaches from genome-wide association studies related to various epigenetic clocks (GrimAge, HannumAge, PhenoAge, and HorvathAge) and multiple sclerosis, utilizing robust instrumental variables from the Edinburgh DataShare (n = 34,710) and the International Multiple Sclerosis Genetics Consortium (including 24,091 controls and 14,498 cases). We applied the inverse-variance weighted approach as our main method for Mendelian randomization, with additional sensitivity analyses to explore underlying heterogeneity and pleiotropy.</p><p><strong>Results: </strong>Using summary-based Mendelian randomization, we found that HannumAge was associated with multiple sclerosis (OR = 1.071, 95%CI:1.006-1.140, p = 0.033, by inverse-variance weighted). The results suggest that an increase in epigenetic age acceleration of HannumAge promotes the risk of multiple sclerosis. In reverse Mendelian randomization analysis, no evidence of a clear causal association of multiple sclerosis on epigenetic age acceleration was identified.</p><p><strong>Conclusions: </strong>Our Mendelian randomization analysis revealed that epigenetic age acceleration of HannumAge was causally associated with multiple sclerosis, and provided novel insights for further mechanistic and clinical studies of epigenetic age acceleration-mediated multiple sclerosis.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"7"},"PeriodicalIF":4.2,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11780769/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143067782","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive analysis of H3K27me3 LOCKs under different DNA methylation contexts reveal epigenetic redistribution in tumorigenesis.","authors":"Yuan Liang, Mengni Liu, Bingyuan Liu, Benjamin Ziman, Guanjie Peng, Qiong Mao, Xingzhe Wang, Lizhen Jiang, De-Chen Lin, Yueyuan Zheng","doi":"10.1186/s13072-025-00570-0","DOIUrl":"10.1186/s13072-025-00570-0","url":null,"abstract":"<p><strong>Background: </strong>Histone modification H3K27me3 plays a critical role in normal development and is associated with various diseases, including cancer. This modification forms large chromatin domains, known as Large Organized Chromatin Lysine Domains (LOCKs), which span several hundred kilobases.</p><p><strong>Result: </strong>In this study, we identify and categorize H3K27me3 LOCKs in 109 normal human samples, distinguishing between long and short LOCKs. Our findings reveal that long LOCKs are predominantly associated with developmental processes, while short LOCKs are enriched in poised promoters and are most associated with low gene expression. Further analysis of LOCKs in different DNA methylation contexts shows that long LOCKs are primarily located in partially methylated domains (PMDs), particularly in short-PMDs, where they are most likely responsible for the low expressions of oncogenes. We observe that in cancer cell lines, including those from esophageal and breast cancer, long LOCKs shift from short-PMDs to intermediate-PMDs and long-PMDs. Notably, a significant subset of tumor-associated long LOCKs in intermediate- and long-PMDs exhibit reduced H3K9me3 levels, suggesting that H3K27me3 compensates for the loss of H3K9me3 in tumors. Additionally, we find that genes upregulated in tumors following the loss of short LOCKs are typically poised promoter genes in normal cells, and their transcription is regulated by the ETS1 transcription factor.</p><p><strong>Conclusion: </strong>These results provide new insights into the role of H3K27me3 LOCKs in cancer and underscore their potential impact on epigenetic regulation and disease mechanisms.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"6"},"PeriodicalIF":4.2,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tissue-specific roles of de novo DNA methyltransferases.","authors":"Dániel Márton Tóth, Flóra Szeri, Mária Ashaber, Muhyiddeen Muazu, Lóránt Székvölgyi, Tamás Arányi","doi":"10.1186/s13072-024-00566-2","DOIUrl":"10.1186/s13072-024-00566-2","url":null,"abstract":"<p><p>DNA methylation, catalyzed by DNA methyltransferases (DNMT), plays pivotal role in regulating embryonic development, gene expression, adaption to environmental stress, and maintaining genome integrity. DNMT family consists of DNMT1, DNMT3A, DNMT3B, and the enzymatically inactive DNMT3L. DNMT3A and DNMT3B establish novel methylation patterns maintained by DNMT1 during replication. Genetic variants of DNMT3A and DNMT3B cause rare diseases such as Tatton-Brown-Rahman and ICF syndromes. Additionally, somatic mutations cause common conditions such as osteoarthritis, osteoporosis, clonal hematopoiesis of indeterminate potential (CHIP), hematologic malignancies, and cancer. While DNMTs have been extensively studied in vitro, in early development and in disease, their detailed physiologic roles remain less understood as in vivo investigations are hindered by the embryonic or perinatal lethality of the knockout mice. To circumvent this problem, tissue-specific Dnmt3a and Dnmt3b knockouts were engineered. This review explores their diverse molecular roles across various organs and cell types and characterizes the phenotype of the knockout mice. We provide a comprehensive collection of over forty tissue-specific knockout models generated by cre recombinase. We highlight the distinct functions of DNMT3A and DNMT3B in germ cells, early development, uterus, hematopoietic differentiation, musculoskeletal development, visceral organs, and nervous system. Our findings indicate that DNMT3A primarily regulates hematopoietic differentiation, while DNMT3B is crucial for cartilage homeostasis and ossification. We emphasize the context-dependent roles of DNMT3A and DNMT3B and demonstrate that they also complement DNMT1 maintenance methyltransferase activity. Overall, the expression patterns of DNMTs across tissues provide insights into potential therapeutic applications for treating neurologic diseases, cancer, and osteoporosis.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"5"},"PeriodicalIF":4.2,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11740433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acquired sperm hypomethylation by gestational arsenic exposure is re-established in both the paternal and maternal genomes of post-epigenetic reprogramming embryos.","authors":"Keiko Nohara, Takehiro Suzuki, Kazuyuki Okamura, Tomoko Kawai, Kazuhiko Nakabayashi","doi":"10.1186/s13072-025-00569-7","DOIUrl":"10.1186/s13072-025-00569-7","url":null,"abstract":"<p><strong>Background: </strong>DNA methylation plays a crucial role in mammalian development. While methylome changes acquired in the parental genomes are believed to be erased by epigenetic reprogramming, accumulating evidence suggests that methylome changes in sperm caused by environmental factors are involved in the disease phenotypes of the offspring. These findings imply that acquired sperm methylome changes are transferred to the embryo after epigenetic reprogramming. However, our understanding of this process remains incomplete. Our previous study showed that arsenic exposure of F0 pregnant mice paternally increased tumor incidence in F2 offspring. The sperm methylome of arsenic-exposed F1 males exhibited characteristic features, including enrichment of hypomethylated cytosines at the promoters of retrotransposons LINEs and LTRs. Hypomethylation of retrotransposons is potentially detrimental. Determining whether these hypomethylation changes in sperm are transferred to the embryo is important in confirming the molecular pathway of intergenerational transmission of paternal effects of arsenic exposure.</p><p><strong>Results: </strong>We investigated the methylome of F2 male embryos after epigenetic reprogramming by reduced representation bisulfite sequencing (RRBS) and allele-specific analysis. To do so, embryos were obtained by crossing control or gestationally arsenic-exposed F1 males (C3H/HeN strain) with control females (C57BL/6 strain). The results revealed that the methylome of F2 embryos in the arsenic group was globally hypomethylated and enriched for hypomethylated cytosines in certain genomic regions, including LTR and LINE, as observed in F1 sperm of the arsenic group. Unexpectedly, the characteristic methylome features were detected not only in the paternal genome but also in the maternal genome of embryos. Furthermore, these methylation changes were found to rarely occur at the same positions between F1 sperm and F2 embryos.</p><p><strong>Conclusions: </strong>The results of this study revealed that the characteristics of arsenic-induced methylome changes in F1 sperm are reproduced in both the paternal and maternal genomes of post-epigenetic reprogramming embryos. Furthermore, the results suggest that this re-establishment is achieved in collaboration with other factors that mediate region-specific methylation changes. These results also highlight the possibility that arsenic-induced sperm methylome changes could contribute to the development of disease predisposition in offspring.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"4"},"PeriodicalIF":4.2,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11737231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143014837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crosstalk between non-coding RNAs and programmed cell death in colorectal cancer: implications for targeted therapy.","authors":"Seyed Reza Taha, Mehdi Karimi, Bahar Mahdavi, Milad Yousefi Tehrani, Ali Bemani, Shahriar Kabirian, Javad Mohammadi, Sina Jabbari, Meysam Hushmand, Alireza Mokhtar, Mohammad Hossein Pourhanifeh","doi":"10.1186/s13072-024-00560-8","DOIUrl":"10.1186/s13072-024-00560-8","url":null,"abstract":"<p><strong>Background: </strong>Colorectal cancer (CRC) remains one of the most common causes of cancer-related mortality worldwide. Its progression is influenced by complex interactions involving genetic, epigenetic, and environmental factors. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have been identified as key regulators of gene expression, affecting diverse biological processes, notably programmed cell death (PCD).</p><p><strong>Objective: </strong>This review aims to explore the relationship between ncRNAs and PCD in CRC, focusing on how ncRNAs influence cancer cell survival, proliferation, and treatment resistance.</p><p><strong>Methods: </strong>A comprehensive literature analysis was conducted to examine recent findings on the role of ncRNAs in modulating various PCD mechanisms, including apoptosis, autophagy, necroptosis, and pyroptosis, and their impact on CRC development and therapeutic response.</p><p><strong>Results: </strong>ncRNAs were found to significantly regulate PCD pathways, impacting tumor growth, metastasis, and treatment sensitivity in CRC. Their influence on these pathways highlights the potential of ncRNAs as biomarkers for early CRC detection and as targets for innovative therapeutic interventions.</p><p><strong>Conclusion: </strong>Understanding the involvement of ncRNAs in PCD regulation offers new insights into CRC biology. The targeted modulation of ncRNA-PCD interactions presents promising avenues for personalized cancer treatment, which may improve patient outcomes by enhancing therapeutic effectiveness and reducing resistance.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"3"},"PeriodicalIF":4.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11734566/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142985200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"H3K9 post-translational modifications regulate epiblast/primitive endoderm specification in rabbit blastocysts.","authors":"Wilhelm Bouchereau, Hong-Thu Pham, Worawalan Samruan, Van-Hong Vu, Thierry Joly, Marielle Afanassieff, Pierre Savatier, Rangsun Parnpai, Nathalie Beaujean","doi":"10.1186/s13072-025-00568-8","DOIUrl":"10.1186/s13072-025-00568-8","url":null,"abstract":"<p><p>Post-translational modifications of histone H3 on lysine 9, specifically acetylation (H3K9ac) and tri-methylation (H3K9me3), play a critical role in regulating chromatin accessibility. However, the role of these modifications in lineage segregation in the mammalian blastocyst remains poorly understood. We demonstrate that di- and tri-methylation marks, H3K9me2 and H3K9me3, decrease during cavitation and expansion of the rabbit blastocyst. Notably, H3K9me3 levels are particularly low in inner cell mass cells at the onset of blastocyst formation but increase again just before gastrulation. Conversely, H3K9ac is abundant in early blastocyst stages but decreases during the transition from the inner cell mass to the epiblast. These distinct distribution patterns correlate with high expression levels of methyltransferases (EHMT1, EHMT2, SETDB1) and deacetylases (HDAC1, HDAC2, HDAC5) in expanding blastocysts. Functionally, inhibiting H3K9me2/3 through an EHMT1/2 inhibitor disrupts primitive endoderm segregation, whereas enhancing histone acetylation (including H3K9ac) using a class I HDAC inhibitor promotes epiblast expansion at the expense of the primitive endoderm. These modifications impact the expression of genes associated with pluripotency and lineage determination, underscoring the importance of H3K9 modifications in embryonic cell fate decisions.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"2"},"PeriodicalIF":4.2,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11727677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of genetic diversity, epigenetic regulation, and sex-based differences in HIV cure research: a comprehensive review.","authors":"Punitha Letchumanan, Kumitaa Theva Das","doi":"10.1186/s13072-024-00564-4","DOIUrl":"10.1186/s13072-024-00564-4","url":null,"abstract":"<p><p>Despite significant advances in HIV treatment, a definitive cure remains elusive. The first-in-human clinical trial of Excision BioTherapeutics' CRISPR-based HIV cure, EBT-101, demonstrated safety but failed to prevent viral rebound. These outcomes may result from the interplay of several factors. Growing evidence indicates that intricate epigenetic modifications play a major role in the persistence of HIV latency, presenting a significant barrier to eradication efforts and causing viral rebound after ART discontinuation. Current strategies to purge the latent reservoir involve LRAs that reactivate latent proviruses. However, their clinical success is hindered by the heterogeneity of HIV reservoirs and the virus's diverse pathways. Additionally, RNA modifications like N6-methyladenosine (m^6 A) methylation influence HIV biology beyond transcriptional control, affect RNA stability, splicing, and translation, which could enhance therapeutic efficacy. The regulatory framework of chromatin dynamics is also key to understanding viral latency and reactivation, such as Vpr's role in reactivating latent HIV by targeting HDACs. Sex-specific factors were also shown to play an important role with females, showing stronger early immune responses and higher representation among elite controllers. This review addresses the multifaceted challenges of HIV cure research, focusing on genetic diversity, epigenetic regulation, RNA modifications, chromatin remodeling, and sex-specific factors. By integrating insights into these aspects, this paper aims to advance our understanding of HIV cure strategies and highlight directions for future research.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"18 1","pages":"1"},"PeriodicalIF":4.2,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11697457/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Shedding light on DNA methylation and its clinical implications: the impact of long-read-based nanopore technology.","authors":"Alexandra Chera, Mircea Stancu-Cretu, Nicolae Radu Zabet, Octavian Bucur","doi":"10.1186/s13072-024-00558-2","DOIUrl":"10.1186/s13072-024-00558-2","url":null,"abstract":"<p><p>DNA methylation is an essential epigenetic mechanism for regulation of gene expression, through which many physiological (X-chromosome inactivation, genetic imprinting, chromatin structure and miRNA regulation, genome defense, silencing of transposable elements) and pathological processes (cancer and repetitive sequences-associated diseases) are regulated. Nanopore sequencing has emerged as a novel technique that can analyze long strands of DNA (long-read sequencing) without chemically treating the DNA. Interestingly, nanopore sequencing can also extract epigenetic status of the nucleotides (including both 5-Methylcytosine and 5-hydroxyMethylcytosine), and a large variety of bioinformatic tools have been developed for improving its detection properties. Out of all genomic regions, long read sequencing provides advantages in studying repetitive elements, which are difficult to characterize through other sequencing methods. Transposable elements are repetitive regions of the genome that are silenced and usually display high levels of DNA methylation. Their demethylation and activation have been observed in many cancers. Due to their repetitive nature, it is challenging to accurately estimate DNA methylation levels within transposable elements using short sequencing technologies. The advantage to sequence native DNA (without PCR amplification biases or harsh bisulfite treatment) and long and ultra long reads coupled with epigenetic states of the DNA allows to accurately estimate DNA methylation levels in transposable elements. This is a big step forward for epigenomic studies, and unsolved questions regarding gene expression and transposable elements silencing through DNA methylation can now be answered.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"17 1","pages":"39"},"PeriodicalIF":4.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11684317/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142903916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dissecting the Kaiso binding profile in clear renal cancer cells.","authors":"Alexey Starshin, Pavel Abramov, Yaroslava Lobanova, Fedor Sharko, Galina Filonova, Dmitry Kaluzhny, Daria Kaplun, Igor Deyev, Alexander Mazur, Egor Prokchortchouk, Svetlana Zhenilo","doi":"10.1186/s13072-024-00565-3","DOIUrl":"10.1186/s13072-024-00565-3","url":null,"abstract":"<p><strong>Background: </strong>There has been a notable increase in interest in the transcriptional regulator Kaiso, which has been linked to the regulation of clonal hematopoiesis, myelodysplastic syndrome, and tumorigenesis. Nevertheless, there are no consistent data on the binding sites of Kaiso in vivo in the genome. Previous ChIP-seq analyses for Kaiso contradicted the accumulated data of Kaiso binding sites obtained in vitro. Here, we studied this discrepancy by characterizing the distribution profile of Kaiso binding sites in Caki-1 cells using Kaiso-deficient cells as a negative control, and compared its pattern on chromatin with that in lymphoblastoid cell lines.</p><p><strong>Results: </strong>We employed Caki-1 kidney carcinoma cells and their derivative, which lacks the Kaiso gene, as a model system to identify the genomic targets of Kaiso. The principal binding motifs for Kaiso are CGCG and CTGCNAT, with 60% of all binding sites containing both sequences. The significance of methyl-DNA binding activity was confirmed through examination of the genomic distribution of the E535A mutant variant of Kaiso, which cannot bind methylated DNA in vitro but is able to interact with CTGCNA sequences. Our findings indicate that Kaiso is present at CpG islands with a preference for methylated ones. We identified Kaiso target genes whose methylation and transcription are dependent on its expression. Furthermore, Kaiso binding sites are enriched at CpG islands, with partial methylation at the 5' and/or 3' boundaries. We discovered CpG islands exhibiting wave-like methylation patterns, with Kaiso detected in the majority of these areas. Similar data were obtained in other cell lines.</p><p><strong>Conclusion: </strong>The present study delineates the genomic distribution of Kaiso in cancer cells, confirming its role as a factor with a complex mode of DNA binding and a strong association with CpG islands, particularly with methylated and eroded CpG islands, revealing a new potential Kaiso target gene-SQSTM1, involved in differentiation of acute myeloid leukemia cells. Furthermore, we discovered the existence of a new class of CpG islands characterized by wave-like DNA methylation.</p>","PeriodicalId":49253,"journal":{"name":"Epigenetics & Chromatin","volume":"17 1","pages":"38"},"PeriodicalIF":4.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}