title: Deciphering the transcriptional regulation of microRNA genes in humans with ACTLocater.
abstract: Understanding the transcriptional regulation of microRNAs (miRNAs) is extremely important for determining the specific roles they play in signaling cascades. However, precise identification of transcription factor binding sites (TFBSs) orchestrating the expressions of miRNAs remains a challenge. By combining accessible chromatin sequences of 12 cell types released by the ENCODE Project, we found that a significant fraction (~80%) of such integrated sequences, evolutionary conserved and in regions upstream of human miRNA genes that are independently transcribed, were preserved across cell types. Accordingly, we developed a computational method, Accessible and Conserved TFBSs Locater (ACTLocater), incorporating this chromatin feature and evolutionary conservation to identify the TFBSs associated with human miRNA genes. ACTLocater achieved high positive predictive values, as revealed by the experimental validation of FOXA1 predictions and by the comparison of its predictions of some other transcription factors (TFs) to empirical ChIP-seq data. Most notably, ACTLocater was widely applicable as indicated by the successful prediction of TF → miRNA interactions in cell types whose chromatin accessibility profiles were not incorporated. By applying ACTLocater to TFs with characterized binding specificities, we compiled a novel repository of putative TF → miRNA interactions and displayed it in ACTViewer, providing a promising foundation for future investigations to elucidate the regulatory mechanisms of miRNA transcription in humans.
authors.affiliation: Key Laboratory of Gene Engineering of the Ministry of Education, State Key Laboratory for Biocontrol, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
authors.forename: Zhen-Dong
authors.initials: ZD
authors.lastname: Xiao
authors.forename: Li-Ting
authors.initials: LT
authors.lastname: Diao
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.forename: Mian-Bo
authors.initials: MB
authors.lastname: Huang
authors.forename: Yong-Jin
authors.initials: YJ
authors.lastname: Deng
authors.forename: Hui
authors.initials: H
authors.lastname: Zhou
authors.forename: Liang-Hu
authors.initials: LH
authors.lastname: Qu
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry; D019295:Computational Biology / Q000379:methods*; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D050436:Regulatory Elements, Transcriptional; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D002843:Chromatin; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D035683:MicroRNAs; D014157:Transcription Factors