Identification and function of TEAD1 regulated enhancer in HepG2 cells

Abstract

Background Recent studies have shown that regulatory networks constituted by TFs, enhancer, and miRNAs is crucial for transcriptional regulation and progression in cancer. However, it is unclear whether TEAD1, a cancer-related transcription factor, is involved in enhancer-miRNA network and participates in tumorigenesis and development of hepatocellular carcinoma (HCC). Methods and Results In this study, we first identified 14,286 active enhancers through integrating CAGE-seq and GRO-seq of HepG2, and confirmed that these active enhancers have previously approved features. Moreover, 2,550 enhancers that bound by TEAD1 (EnhTEAD1) were identified through combining 35,883 TEAD1-DNA binding sites. Furthermore, in order to conveniently study the function of TEAD1-enhancer, we divided the enhancers into two categories by whether they are combined with TEAD1: EnhTEAD1 and Enhno-TEAD1. We found that the expression of eRNA (enhancer RNA) and markers of active enhancers (H3K27ac, H3K4me1 and H3K4me3) were significantly higher on EnhTEAD1 than on Enhno-TEAD1. In addition, we suggest that TEAD1 may function as a co-factor with several TFs (GATA4, HNF4A, YY1 and CTCF) and promotes chromosomal accessibility and spatial looping of EnhTEAD1. We performed the small RNA sequencing after interfering with TEAD1 by siRNA in the HCC HepG2 cells. Totally, 68 EnhTEAD1-regulated differently expressed miRNAs interactions (EnhTEAD1-miRNAs) were obtained by RNA-seq and Hi-C. Finally, we found that these EnhTEAD1-miRNAs were significantly involved in kinds of cancer-related pathways and biological processes . Conclusion In summary, this study elucidates the regulation mechanism of EnhTEAD1-miRNAs network in HCC, and also provides a new potential target for the further treatment of HCC.