Martina Rimoldi, Ning Wang, Jilin Zhang, Diego Villar, Duncan T. Odom, Jussi Taipale, Paul Flicek, Maša Roller
{"title":"转录因子结合区的 DNA 甲基化模式揭示其功能和进化背景","authors":"Martina Rimoldi, Ning Wang, Jilin Zhang, Diego Villar, Duncan T. Odom, Jussi Taipale, Paul Flicek, Maša Roller","doi":"10.1186/s13059-024-03218-6","DOIUrl":null,"url":null,"abstract":"DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.","PeriodicalId":12611,"journal":{"name":"Genome Biology","volume":null,"pages":null},"PeriodicalIF":10.1000,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts\",\"authors\":\"Martina Rimoldi, Ning Wang, Jilin Zhang, Diego Villar, Duncan T. Odom, Jussi Taipale, Paul Flicek, Maša Roller\",\"doi\":\"10.1186/s13059-024-03218-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.\",\"PeriodicalId\":12611,\"journal\":{\"name\":\"Genome Biology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":10.1000,\"publicationDate\":\"2024-06-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genome Biology\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13059-024-03218-6\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13059-024-03218-6","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
DNA 甲基化是一种重要的表观遗传修饰,在调节基因组功能方面具有多种作用。其水平在整个基因组中具有空间相关性,通常在受抑制区域较高,而在转录因子(TF)结合位点和活性调控区域较低。然而,建立全基因组和 TF 结合位点甲基化模式的机制仍不清楚。在这里,我们使用一种比较方法来研究哺乳动物 DNA 甲基化与 TF 结合进化的关联。具体来说,我们通过实验分析了 DNA 甲基化情况,并将其与已发表的五种不同 TF(CTCF、CEBPA、HNF4A、ONECUT1、FOXA1)在五种哺乳动物(人、猕猴、小鼠、大鼠、狗)肝脏中的占据情况相结合。TF 结合位点的甲基化水平较低,但也常常具有中等甲基化水平。此外,即使核心结合图案中没有 CpGs,结合位点也会受到其更宽结合区域中 CpGs 甲基化状态的影响。通过分类和聚类方法,我们提取了 TF 结合区 DNA 甲基化水平的不同物种保守模式。CEBPA、HNF4A、ONECUT1 和 FOXA1 具有相同的甲基化模式,而 CTCF 的甲基化模式则有所不同。这些模式表征了 TF 结合区域的不同功能和染色质景观。利用我们的系统发育框架,我们发现在进化过程中 TF 占位丧失后 DNA 甲基化增殖,这表明进化是协调进行的。此外,每种甲基化模式都有自己的进化轨迹,反映了其基因组背景。我们的表观基因组分析表明了 DNA 甲基化在跨物种 TF 结合变化中的作用,包括特定的 DNA 甲基化图谱描述了 TF 结合的特征,并与其调控活性、染色质环境和进化轨迹相关联。
DNA methylation patterns of transcription factor binding regions characterize their functional and evolutionary contexts
DNA methylation is an important epigenetic modification which has numerous roles in modulating genome function. Its levels are spatially correlated across the genome, typically high in repressed regions but low in transcription factor (TF) binding sites and active regulatory regions. However, the mechanisms establishing genome-wide and TF binding site methylation patterns are still unclear. Here we use a comparative approach to investigate the association of DNA methylation to TF binding evolution in mammals. Specifically, we experimentally profile DNA methylation and combine this with published occupancy profiles of five distinct TFs (CTCF, CEBPA, HNF4A, ONECUT1, FOXA1) in the liver of five mammalian species (human, macaque, mouse, rat, dog). TF binding sites are lowly methylated, but they often also have intermediate methylation levels. Furthermore, biding sites are influenced by the methylation status of CpGs in their wider binding regions even when CpGs are absent from the core binding motif. Employing a classification and clustering approach, we extract distinct and species-conserved patterns of DNA methylation levels at TF binding regions. CEBPA, HNF4A, ONECUT1, and FOXA1 share the same methylation patterns, while CTCF's differ. These patterns characterize alternative functions and chromatin landscapes of TF-bound regions. Leveraging our phylogenetic framework, we find DNA methylation gain upon evolutionary loss of TF occupancy, indicating coordinated evolution. Furthermore, each methylation pattern has its own evolutionary trajectory reflecting its genomic contexts. Our epigenomic analyses indicate a role for DNA methylation in TF binding changes across species including that specific DNA methylation profiles characterize TF binding and are associated with their regulatory activity, chromatin contexts, and evolutionary trajectories.
Genome BiologyBiochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍:
Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens.
With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category.
Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.