Integrative pan cancer analysis reveals epigenomic variation in cancer type and cell specific chromatin domains

Lijin K Gopi,Benjamin L Kidder

doi:10.1038/s41467-021-21707-1

Lijin K Gopi, Benjamin L Kidder

Open Access

https://doi.org/10.1038/s41467-021-21707-1

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Abstract

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. While the NCI-60 panel represents a diverse set of human cancer cell lines that has been used to screen chemical compounds, a comprehensive epigenomic atlas of these cells has been lacking. Here, we report an integrative analysis of 60 human cancer epigenomes, representing a catalog of activating and repressive histone modifications. We identify genome-wide maps of canonical sharp and broad H3K4me3 domains at promoter regions of tumor suppressors, H3K27ac-marked conventional enhancers and super enhancers, and widespread inter-cancer and intra-cancer specific variability in H3K9me3 and H4K20me3-marked heterochromatin domains. Furthermore, we identify features of chromatin states, including chromatin state switching along chromosomes, correlation of histone modification density with genetic mutations, DNA methylation, enrichment of DNA binding motifs in regulatory regions, and gene activity and inactivity. These findings underscore the importance of integrating epigenomic maps with gene expression and genetic variation data to understand the molecular basis of human cancer. Our findings provide a resource for mining epigenomic maps of human cancer cells and for identifying epigenetic therapeutic targets.

Highlights

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation
To interrogate the global epigenetic landscapes across 9 types of cancer represented in the National Cancer Institute-60 (NCI-60) panel (Supplementary Data 1) we performed chromatin immunoprecipitation followed by nextgeneration sequencing (ChIP-Seq)[23,24] to profile activating and repressive histone modifications including H3K4me[3], H3K27ac, H3K9me[3], and H4K20me[3]
H3K4me[3] is predominantly enriched at promoters and transcriptional start sites (TSS) of highly expressed genes[23], where it is presumed to serve as a platform for RNA polymerase II (RNAPII) binding and target gene activation[25,26,27]

Summary

Introduction

Epigenetic mechanisms contribute to the initiation and development of cancer, and epigenetic variation promotes dynamic gene expression patterns that facilitate tumor evolution and adaptation. We identify features of chromatin states, including chromatin state switching along chromosomes, correlation of histone modification density with genetic mutations, DNA methylation, enrichment of DNA binding motifs in regulatory regions, and gene activity and inactivity These findings underscore the importance of integrating epigenomic maps with gene expression and genetic variation data to understand the molecular basis of human cancer. Because cancer cells exhibit alterations in chromatin structure and distributions of covalent histone modifications across the genome relative to normal cells[18,19,20], constructing global maps of histone modifications for the NCI-60 panel by systematic high-throughput profiling will be instrumental in annotating cis-regulatory elements, demarcating cancer genomes into euchromatin and heterochromatin domains, and evaluating correlations between histone modifications and gene activity, or orthogonal genetic or epigenetic features such as DNA mutation or DNA methylation, respectively. These findings provide a framework to interrogate human cancer epigenomes using histone modification data

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