Abstract B03: Loss of the Polycomb mark at bivalent promoters leads to activation of intestinal stem cell genes in colorectal cancer

Abstract

Abstract During tumor formation, transcription of many genes becomes deregulated. In order to elucidate epigenetic mechanisms responsible for this phenomenon, we analyzed genome-wide patterns of several histone marks, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) in human stage II colorectal cancer and matching normal tissue samples. By using liquid chromatography—mass spectrometry (LC-MS/MS), we determined that colon tumors have strongly reduced global levels of 5hmC. However, Tet-assisted bisulfite sequencing showed that site-specific loss of 5hmC in tumors is not associated with localized aberrant CpG island hypermethylation. We observed that DNA hypermethylation is generally targeted to bivalent promoters, which loose H3K27me3 and the associated genes are repressed effectively. Importantly, loss of H3K27me3 at bivalent promoters is not always coupled with gain of 5mC. Instead, H3K27me3 loss is also frequently associated with activation of intestinal stem cell markers and stem cell regulators including LGR5, SOX9, CDX1, CDX2, KLF5, and SALL4 as well as activation of many genes linked to colorectal cancer progression such as MET, CLDN1, PTGS2 (COX-2) and CCND1 (cyclin D1). Activation of these genes correlates with accumulation of the active chromatin mark H3K4me3 at their promoters. Our study demonstrates two distinct features of H3K27me3 loss in cancer. Loss of H3K27me3 at bivalent genes can be accompanied by either gain of 5mC and strong repression or by persistence or gain of H3K4me3 and gene activation. We propose that instability of H3K27me3 coupled with selection for tumor-promoting events plays a major role in colorectal cancer progression most notably by causing activation of cancer driving genes including factors involved in stem cell maintenance. Citation Format: Maria A. Hahn, Arthur X. Li, Xiwei Wu, Daniel W. Rosenberg, Gerd P. Pfeifer. Loss of the Polycomb mark at bivalent promoters leads to activation of intestinal stem cell genes in colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B03.