Hongying Zhao1, Guanxiong Zhang1, Lin Pang1, Yujia Lan1, Li Wang1, Fulong Yu1, Jing Hu1, Feng Li1, Tingting Zhao2, Yun Xiao3, Xia Li4. 1. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. 2. Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, China. 3. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China; Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Harbin, China. Electronic address: xiaoyun@ems.hrbmu.edu.cn. 4. College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 150081, China. Electronic address: lixia@hrbmu.edu.cn.
Abstract
BACKGROUND: Epigenetic marks can cooperatively regulate chromatin accessibility and in turn facilitate or impede the binding of regulatory factors to various elements, suggesting their important roles in regulatory circuits. However, it remains elusive as to how epigenetic marks cooperate in the operations of regulatory network. METHODS: Here, we systematically characterized chromatin states of 26 epigenetic marks on different elements of protein-coding genes and miRNAs. We comprehensively analyzed, by using an integrative regulatory network, how cooperation among epigenetic, transcriptional, and post-transcriptional regulations came about. RESULTS: We observed extensive cooperation of epigenetic marks on local functional elements and complex epigenetic patterns corresponding to different biological functions. By identifying the significantly epigenetic state-modified motifs, we found that multiple combinations of epigenetic states were associated with a specific type of motif. Interestingly, miRNA-mediated motifs were linked to stable epigenetic states of downstream targets. Changes in epigenetic states of downstream targets in miRNA-mediated motifs can buffer the effects of upstream regulator on target genes, suggesting that miRNA-mediated motifs require the cooperation of epigenetic marks. CONCLUSIONS: Overall, epigenetic marks are involved in the running of regulatory motifs in the way traffic lights control traffic flows and hence should be part of the architecture of complex regulatory circuits. GENERAL SIGNIFICANCE: We demonstrated a detailed analysis of the cooperation of multiple epigenetic marks and how epigenetic regulation was organized into a human regulatory network. The findings form a basis for further understanding of the complicated roles of epigenetic marks on regulatory circuits.
BACKGROUND: Epigenetic marks can cooperatively regulate chromatin accessibility and in turn facilitate or impede the binding of regulatory factors to various elements, suggesting their important roles in regulatory circuits. However, it remains elusive as to how epigenetic marks cooperate in the operations of regulatory network. METHODS: Here, we systematically characterized chromatin states of 26 epigenetic marks on different elements of protein-coding genes and miRNAs. We comprehensively analyzed, by using an integrative regulatory network, how cooperation among epigenetic, transcriptional, and post-transcriptional regulations came about. RESULTS: We observed extensive cooperation of epigenetic marks on local functional elements and complex epigenetic patterns corresponding to different biological functions. By identifying the significantly epigenetic state-modified motifs, we found that multiple combinations of epigenetic states were associated with a specific type of motif. Interestingly, miRNA-mediated motifs were linked to stable epigenetic states of downstream targets. Changes in epigenetic states of downstream targets in miRNA-mediated motifs can buffer the effects of upstream regulator on target genes, suggesting that miRNA-mediated motifs require the cooperation of epigenetic marks. CONCLUSIONS: Overall, epigenetic marks are involved in the running of regulatory motifs in the way traffic lights control traffic flows and hence should be part of the architecture of complex regulatory circuits. GENERAL SIGNIFICANCE: We demonstrated a detailed analysis of the cooperation of multiple epigenetic marks and how epigenetic regulation was organized into a human regulatory network. The findings form a basis for further understanding of the complicated roles of epigenetic marks on regulatory circuits.