Abstract
ObjectiveThis study aims to identify superenhancer (SE)–transcriptional factor (TF) regulatory network related to eight common malignant tumors based on ChIP-seq data modified by histone H3K27ac in the enhancer region of the SRA database.MethodsH3K27ac ChIP-seq data of eight common malignant tumor samples were downloaded from the SRA database and subjected to comparison with the human reference genome hg19. TFs regulated by SEs were screened with HOMER software. Core regulatory circuitry (CRC) in malignant tumor samples was defined through CRCmapper software and validated by RNA-seq data in TCGA. The findings were substantiated in bladder cancer cell experiments.ResultsDifferent malignant tumors could be distinguished through the H3K27ac signal. After SE identification in eight common malignant tumor samples, 35 SE-regulated genes were defined as malignant tumor-specific. SE-regulated specific TFs effectively distinguished the types of malignant tumors. Finally, we obtained 60 CRC TFs, and SMAD3 exhibited a strong H3K27ac signal in eight common malignant tumor samples. In vitro experimental data verified the presence of a SE–TF regulatory network in bladder cancer, and SE–TF regulatory network enhanced the malignant phenotype of bladder cancer cells.ConclusionThe SE–TF regulatory network with SMAD3 as the core TF may participate in the carcinogenesis of malignant tumors.
Highlights
The superenhancer (SE) regulates gene expression and is characterized by high-density epigenetic modifications associated with transcription factors (TFs), and cofactors [1]
Our study aims to identify and analyze core SEs and TFs in various malignant tumors such as liver cancer, lung cancer, and breast cancer based on H3K27ac Chromatin immunoprecipitation (ChIP)-seq data in the sequence read archive (SRA) database as well as RNA-seq data in The Tumor Genome Atlas (TCGA) database
ChIP-seq data of differential histone modification regions in eight common malignant tumor cell lines were downloaded from the SRA database
Summary
The superenhancer (SE) regulates gene expression and is characterized by high-density epigenetic modifications associated with transcription factors (TFs), and cofactors [1]. The abnormal gene transcription mediated by SEs is essential for maintaining the characteristics of tumor cells [2]. Tumor cells significantly promote the expression of various oncogenes by assembling SE, thereby enhancing their proliferation, invasion, and metastasis [3]. The transcriptional element, for example, bromodomain-containing protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7), has been reportedly the treatment target due to tumor-specific SEs [6]. By chromatin immunoprecipitation and sequencing (ChIP-seq) processing, Oldridge et al found changed polymorphism within one SE element of LIM domain only 1 (LMO1) significantly affected neuroblastoma susceptibility by different binding of gamma-aminobutyrate (GATA) TF or regulation of LMO1 expression, which resulted in oncogenic dependency of neuroblastoma [8]. Oncogenic homeobox B8 (HOXB8) was driven by MYC-regulated SEs and enhanced colorectal cancer invasiveness through BTB and CNC
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