Disturbance of poised chromatin coincides with increased expression of developmental genes in cancer

Abstract

Poised (bivalent or paused) chromatin comprises activating and repressing histone modifications at the same location (Voigt et al., 2013). This combination of epigenetic marks keeps genes expressed at low levels but poised for rapid activation (Margaritis and Holstege, 2008; Mikkelsen et al., 2007). Typically, DNA at poised promoters carries low levels of methylation in normal cells (Meissner et al., 2008; Roadmap Epigenomics Consortium et al., 2015), but frequently shows elevated methylation levels in cancer samples (Hinoue et al., 2012; Gal-Yam et al., 2008; Ohm et al., 2007; Rodriguez et al., 2008; Easwaran et al., 2012). Although higher levels of methylation are normally associated with transcriptional silencing, recently counter-intuitive positive correlations between methylation and expression levels have been reported for two cancer types (Hahn et al., 2014; Kretzmer et al.,). Here, we analyze one of the largest combined expression and methylation data-sets to date, comprising over 5,000 samples and demonstrate that the hypermethylation of poised chromatin in conjunction with up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects developmental genes and transcription factors, including many genes implicated in cancer. From analysis of 7,000 methylation data sets, we built a universal classifier that can identify cancer samples solely from the hypermethylation status of originally poised chromatin. We reason that the alteration of the epigenetic status of poised chromatin is intimately linked to tumorigenesis.