Coordinated Action Of Histone Modification And MicroRNA Regulations In Human Genome

Regulation of gene expression is a relatively complex process, which could be impacted by various epigenetic modification and non-coding RNAs. Both histone modifications and microRNAs (miRNAs) play pivotal role in gene expression regulation. Although numerous studies have been devoted to explore the gene regulation by miRNA or epigenetic regulations, their coordinated actions have not been comprehensively examined.In this work, we systematically investigated the combinatorial relationship between miRNA and epigenetic regulation by taking advantage of recently published whole genome-wide histone modification data and high quality miRNA targeting data. Those data include mirTarBase high-confident miRNA-mRNA targeting relationship and a number of ChIP-Seq based different type histone modification collected in several cell lines. We observed relationship between miRNA and histone modification primarily in CD4+ T cell, data in which contains the most complete histone modification type.The results showed that miRNA targets have distinct histone modification patterns compared with non-targets in their promoter regions. Most of 39 histone modifications of miRNA targets have significantly different signal in promoter regions compared to non-target genes. Only few methylations of histone proteins have higher signal in non-targets genes while other histone modification have higher miRNA target genes. Those results indicate a concentration of histone modification pattern in miRNA target genes.Based on this finding, we proposed a machine learning approach to fit predictive models on the task to discern whether a gene is targeted by a specific miRNA. We found a considerable advantage in both sensitivity and specificity in diverse human cell lines. The SVM model takes high confidence miRNA target genes as training set. After screen miRNA target specific histone modification pattern, SVM give predictions of target genes of each miRNA. Compared to other sequenced bases software result, SVM give a number of novel miRNA target as well as potential new miRNA target sites located in gene intron and coding regions.Finally, we found that our predicted miRNA targets are consistently annotated with Gene Ontology terms, which may imply miRNA target genes predicted by SVM model likely located in similar biological processes.Our work is the first genome-wide investigation of the coordinated action of miRNA and histone modification regulations, which provides a guide to deeply understand the complexity of transcriptional regulation.