DNA methylation regulates discrimination of enhancers from promoters through a H3K4me1-H3K4me3 seesaw mechanism

BMC Genomics

Research Article

Daniela Gerovska¹  Marcos J. Araúzo-Bravo²  Hamidreza Chitsaz³  Ali Sharifi-Zarchi⁴  Kenjiro Adachi⁵  Hans R. Schöler⁶  Mehdi Totonchi⁷  Hossein Baharvand⁸  Ryan J. Taft⁹  Mehdi Sadeghi^1,10  Hamid Pezeshk^1,11 

[1] Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain;Computational Biology and Systems Biomedicine, Biodonostia Health Research Institute, 20014, San Sebastián, Spain;Computational Biology and Bioinformatics Group, Max Planck Institute for Molecular Biomedicine, Münster, Germany;IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain;Computer Science Department, Colorado State University, Fort Collins, CO, USA;Department of Bioinformatics, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran;Computer Science Department, Colorado State University, Fort Collins, CO, USA;Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Department of Computer Engineering, Sharif University of Technology, Tehran, Iran;Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany;Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany;Medical Faculty, University of Münster, Münster, Germany;Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran;Department of Developmental Biology, University of Science and Culture, Tehran, Iran;Illumina Inc., San Diego, USA;School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran;National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran;School of Mathematics, Statistics and Computer Science, College of Science, University of Tehran, Tehran, Iran;School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran;

关键词: DNA methylation;    Histone modifications;    Promoters;    Enhancers;    H3K4me1;    H3K4me3;    Computational epigenomics;    Next generation sequencing;   

DOI  :  10.1186/s12864-017-4353-7

 received in 2017-03-21, accepted in 2017-11-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDNA methylation at promoters is largely correlated with inhibition of gene expression. However, the role of DNA methylation at enhancers is not fully understood, although a crosstalk with chromatin marks is expected. Actually, there exist contradictory reports about positive and negative correlations between DNA methylation and H3K4me1, a chromatin hallmark of enhancers.ResultsWe investigated the relationship between DNA methylation and active chromatin marks through genome-wide correlations, and found anti-correlation between H3K4me1 and H3K4me3 enrichment at low and intermediate DNA methylation loci. We hypothesized “seesaw” dynamics between H3K4me1 and H3K4me3 in the low and intermediate DNA methylation range, in which DNA methylation discriminates between enhancers and promoters, marked by H3K4me1 and H3K4me3, respectively. Low methylated regions are H3K4me3 enriched, while those with intermediate DNA methylation levels are progressively H3K4me1 enriched. Additionally, the enrichment of H3K27ac, distinguishing active from primed enhancers, follows a plateau in the lower range of the intermediate DNA methylation level, corresponding to active enhancers, and decreases linearly in the higher range of the intermediate DNA methylation. Thus, the decrease of the DNA methylation switches smoothly the state of the enhancers from a primed to an active state. We summarize these observations into a rule of thumb of one-out-of-three methylation marks: “In each genomic region only one out of these three methylation marks {DNA methylation, H3K4me1, H3K4me3} is high. If it is the DNA methylation, the region is inactive. If it is H3K4me1, the region is an enhancer, and if it is H3K4me3, the region is a promoter”. To test our model, we used available genome-wide datasets of H3K4 methyltransferases knockouts. Our analysis suggests that CXXC proteins, as readers of non-methylated CpGs would regulate the “seesaw” mechanism that focuses H3K4me3 to unmethylated sites, while being repulsed from H3K4me1 decorated enhancers and CpG island shores.ConclusionsOur results show that DNA methylation discriminates promoters from enhancers through H3K4me1-H3K4me3 seesaw mechanism, and suggest its possible function in the inheritance of chromatin marks after cell division. Our analyses suggest aberrant formation of promoter-like regions and ectopic transcription of hypomethylated regions of DNA. Such mechanism process can have important implications in biological process in where it has been reported abnormal DNA methylation status such as cancer and aging.

【 授权许可】

CC BY   
© The Author(s). 2017