Abstract
Epigenetic modifications play critical roles in modulating gene expression, yet their roles in regulatory networks in human cell lines remain poorly characterized. We integrated multiomics data to construct directed regulatory networks with nodes and edges labeled with chromatin states in human cell lines. We observed extensive association of diverse chromatin states and network motifs. The gene expression analysis showed that diverse chromatin states of coherent type-1 feedforward loop (C1-FFL) and incoherent type-1 feedforward loops (I1-FFL) contributed to the dynamic expression patterns of targets. Notably, diverse chromatin state compositions could help C1- or I1-FFL to control a large number of distinct biological functions in human cell lines, such as four different types of chromatin state compositions cooperating with K562-associated C1-FFLs controlling “regulation of cytokinesis,” “G1/S transition of mitotic cell cycle,” “DNA recombination,” and “telomere maintenance,” respectively. Remarkably, we identified six chromatin state-marked C1-FFL instances (HCFC1-NFYA-ABL1, THAP1-USF1-BRCA2, ZNF263-USF1-UBA52, MYC-ATF1-UBA52, ELK1-EGR1-CCT4, and YY1-EGR1-INO80C) could act as prognostic biomarkers of acute myelogenous leukemia though influencing cancer-related biological functions, such as cell proliferation, telomere maintenance, and DNA recombination. Our results will provide novel insight for better understanding of chromatin state-mediated gene regulation and facilitate the identification of novel diagnostic and therapeutic biomarkers of human cancers.
Highlights
These authors contributed : Li Wang, Hongying Zhao, Jing Li, Yingqi XuA variety of posttranslation modifications of histones were reported including histone acetylation and methylation
By integrating multiomics data of embryonic stem cells (H1-hESC), lymphoblastoid (GM12878), myelogenous leukemia (K562), and hepatocellular carcinoma (HepG2), we constructed chromatin state-marked transcriptional regulatory network, in which nodes and edges were assigned with specific chromatin states in each of the four cell lines
We constructed regulatory networks labeled with chromatin states in human cell lines and performed a systemic analysis of network motifs marked by chromatin states
Summary
These authors contributed : Li Wang, Hongying Zhao, Jing Li, Yingqi XuA variety of posttranslation modifications of histones were reported including histone acetylation and methylation. H3 lysine 36 dimethylation is associated with increased transcription by counteracting PRC2-dependent histone H3 lysine 27 trimethylation (H3K27me). Combinations of histone modifications (acetylation or methylation) could defined open or closed chromatin states which provide information about the transcriptional activity and regulatory element function of the associated DNA across human genome [2, 3]. Emerging evidence implicated that the levels of histone modifications changed dynamically across different human cell types and disease status [1]. The epigenetic regulators such as “writers” and “erasers” of epigenetic marks were highly mutated in human cancer. Aberrant histone modification patterns during tumorigenesis frequently occurred and could trigger pathogenic misregulation of gene expression or genome instability
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