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.
Highlights
In the 1940s, the term epigenetics was first introduced to describe the interaction between a phenotype and the environment (Waddington, 2012)
By applying the prostate reference epigenome to functionally annotate genetic variants associated with prostate cancer, we identified two GWAS SNPs in prostate enhancers that may disrupt androgen receptor (AR) binding and the target gene regulatory network, thereby providing a mechanistic hypothesis regarding genetic predisposition for the disease
For ChIP-seq quality assurance, we calculated the number of usable fragments, the fraction of reads in peaks (FRiP), percentage of reads marked as duplicates, percentage of reads within blacklist regions, and relative cross-coverage scores (Supplementary Table 1)
Summary
In the 1940s, the term epigenetics was first introduced to describe the interaction between a phenotype and the environment (Waddington, 2012). Interest in epigenetics has been fueled by accumulating evidence that the mechanisms are associated with various human diseases and developmental stages This includes most types of cancer, and autoimmune, cardiovascular, and hereditary disorders (van der Harst et al, 2017; Cavalli and Heard, 2019). The NIH Roadmap Epigenomics Consortium integrated epigenomic maps to develop a database of tissue-specific functional elements, with distinct chromatin states and generated reference epigenomes for 127 human tissues and primary cells (Roadmap Epigenomics Consortium et al, 2015) These maps have been extensively used to gain an in-depth understanding of the role of epigenomic modifications underlying diverse human traits, as well as gene regulation, cell differentiation, and tumorigenesis (Chen et al, 2016; Yu et al, 2016; Pomerantz et al, 2020). Prostate tissues were not included in these initial studies
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