Integrative Epigenome Map of the Normal Human Prostate Provides Insights Into Prostate Cancer Predisposition

Abstract

Cells of all tissues in the human body share almost the exact same DNA sequence, but the epigenomic landscape can be drastically distinct. To improve our understanding of the epigenetic abnormalities in prostate-related diseases, it is important to use the epigenome of normal prostate as a reference. Although previous efforts have provided critical insights into the genetic and transcriptomic features of the normal prostate, a comprehensive epigenome map has been lacking. To address this need, we conducted a Roadmap Epigenomics legacy project integrating six histone marks (H3K4me1, H3K4me3, H3K9me3, H3K36me3, H3K27me3, and H3K27ac) with complete DNA methylome, transcriptome, and chromatin accessibility data to produce a comprehensive epigenome map of normal prostate tissue. Our epigenome map is composed of 18 chromatin states each with unique signatures of DNA methylation, chromatin accessibility, and gene expression. This map provides a high-resolution comprehensive annotation of regulatory regions of the prostate, including 105,593 enhancer and 70,481 promoter elements, which account for 5.3% of the genome. By comparing with other epigenomes, we identified 7,580 prostate-specific active enhancers associated with prostate development. Epigenomic annotation of GWAS SNPs associated with prostate cancers revealed that two out of nine SNPs within prostate enhancer regions destroyed putative androgen receptor (AR) binding motif. A notable SNP rs17694493, might decouple AR’s repressive effect on CDKN2B-AS1 and cell cycle regulation, thereby playing a causal role in predisposing cancer risk. The comprehensive epigenome map of the prostate is valuable for investigating prostate-related diseases.