Research Papers:

An annotated list of bivalent chromatin regions in human ES cells: a new tool for cancer epigenetic research

Franck Court _ and Philippe Arnaud

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Oncotarget. 2017; 8:4110-4124. https://doi.org/10.18632/oncotarget.13746

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Franck Court1,2,3, Philippe Arnaud1,2,3

1CNRS-UMR 6293, Clermont-Ferrand, 63001, France

2INSERM-U1103, Clermont-Ferrand, 63001, France

3Université Clermont Auvergne, GReD Laboratory, Clermont-Ferrand, 63000, France

Correspondence to:

Philippe Arnaud, email: [email protected]

Franck Court, email: [email protected]

Keywords: cancer epigenetics, bivalent chromatin, DNA methylation, human stem cell chromatin signature

Received: September 13, 2016     Accepted: November 23, 2016     Published: December 01, 2016


CpG islands (CGI) marked by bivalent chromatin in stem cells are believed to be more prone to aberrant DNA methylation in tumor cells. The robustness and genome-wide extent of this instructive program in different cancer types remain to be determined. To address this issue we developed a user-friendly approach to integrate the stem cell chromatin signature in customized DNA methylation analyses. We used publicly available ChIP-sequencing datasets of several human embryonic stem cell (hESC) lines to determine the extent of bivalent chromatin genome-wide. We then created annotated lists of high-confidence bivalent, H3K4me3-only and H3K27me3-only chromatin regions. The main features of bivalent regions included localization in CGI/promoters, depletion in retroelements and enrichment in specific histone modifications, including the poorly characterized H3K23me2 mark. Moreover, bivalent promoters could be classified in three clusters based on PRC2 and PolII complexes occupancy. Genes with bivalent promoters of the PRC2-defined cluster displayed the lowest expression upon differentiation. As proof-of-concept, we assessed the DNA methylation pattern of eight types of tumors and confirmed that aberrant cancer-associated DNA hypermethylation preferentially targets CGI characterized by bivalent chromatin in hESCs. We also found that such aberrant DNA hypermethylation affected particularly bivalent CGI/promoters associated with genes that tend to remain repressed upon differentiation. Strikingly, bivalent CGI were the most affected by aberrant DNA hypermethylation in both CpG Island Methylator Phenotype-positive (CIMP+) and CIMP-negative tumors, suggesting that, besides transcriptional silencing in the pre-tumorigenic cells, the bivalent chromatin signature in hESCs is a key determinant of the instructive program for aberrant DNA methylation.

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