Bivalent Epigenetic Control of Oncofetal Gene Expression in Cancer

Abstract

Multiple mechanisms of epigenetic control that include DNA methylation, histone modification, noncoding RNAs, and mitotic gene bookmarking play pivotal roles in stringent gene regulation during lineage commitment and maintenance. Experimental evidence indicates that bivalent chromatin domains, i.e., genome regions that are marked by both H3K4me3 (activating) and H3K27me3 (repressive) histone modifications, are a key property of pluripotent stem cells. Bivalency of developmental genes during the G₁ phase of the pluripotent stem cell cycle contributes to cell fate decisions. Recently, some cancer types have been shown to exhibit partial recapitulation of bivalent chromatin modifications that are lost along with pluripotency, suggesting a mechanism by which cancer cells reacquire properties that are characteristic of undifferentiated, multipotent cells. This bivalent epigenetic control of oncofetal gene expression in cancer cells may offer novel insights into the onset and progression of cancer and may provide specific and selective options for diagnosis as well as for therapeutic intervention.

Keywords: bivalency; cancer; epigenetic control; nuclear structure; oncofetal gene expression.

FIG 1

Emerging role of bivalent chromatin in establishing pluripotent or cancer state of cells. The schematic shows the capacity of pluripotent stem cells to give rise to various tissue types during development. Bivalency appears to contribute to cell fate decisions during the pluripotent stem cell cycle. Studies are needed to establish how much of the bivalent chromatin landscape is recapitulated in induced pluripotent cells. It is increasingly evident that a subpopulation of cancer cells exhibits partial recapitulation of bivalent chromatin domains. This oncofetal epigenetic control of gene expression may be a key determinant for cancer onset and progression.

FIG 2

Partial recapitulation of the oncofetal epigenetic landscape, i.e., reemergence of genes bivalently marked in stem cells, in cancer cells. Heat maps (left) and summarization profiles (right) of H3K4me3 (top) and H3K27me3 (bottom) enrichment in the H7-hESC cell line and in the MCF7 and MDA-231 cell lines in 1,172 H7-hESC bivalent genes are shown. The gene transcription start site (tss) and transcription termination site (tts) are indicated. Note the similarity between MCF7 and H7-hESC with respect to H3K27me3 near promoters and the lack of the same in MDA-MB-231. FE, fold enrichment. (The data in the figure are adapted and modified from reference with permission.)