Epigenetic Regulation of Intestinal Stem Cells and Disease: A Balancing Act of DNA and Histone Methylation

Abstract

Genetic mutations or regulatory failures underlie cellular malfunction in many diseases, including colorectal cancer and inflammatory bowel diseases. However, mutational defects alone fail to explain the complexity of such disorders. Epigenetic regulation-control of gene action through chemical and structural changes of chromatin-provides a platform to integrate multiple extracellular inputs and prepares the cellular genome for appropriate gene expression responses. Coregulation by polycomb repressive complex 2-mediated trimethylation of lysine 27 on histone 3 and DNA methylation has emerged as one of the most influential epigenetic controls in colorectal cancer and many other diseases, but molecular details remain inadequate. Here we review the molecular interplay of these epigenetic features in relation to gastrointestinal development, homeostasis, and disease biology. We discuss other epigenetic mechanisms pertinent to the balance of trimethylation of lysine 27 on histone 3 and DNA methylation and their actions in gastrointestinal cancers. We also review the current molecular understanding of chromatin control in the pathogenesis of inflammatory bowel diseases.

Keywords: Colorectal Cancer; DNA Methylation; Epigenetic Regulation; H3K27me3; Inflammatory Bowel Disease; Intestinal Stem Cells; PRC2.

Figure 1.. Epigenetic interplay involving H3K27 methylation and its consequence on gene expression.

A) PRC2 complex deposits H3K27me3 at hypomethylated gene promoters leading to a repressed state. Such PRC2 based chromatin and gene control is prevalent in facultative heterochromatin located near the center of the nucleus. H3K9me3 decorated constitutive heterochromatin is found along the nuclear periphery. B) Co-occupancy of activating H3K4me3 and repressive H3K27me3 at hypomethylated promoters keeps genes form ‘bivalent’ domains. Genes with such dual histone marking are in poised state with reduced or no gene expression. C) Mutual exclusivity of activation associated H3K36me3 and H3K27me3 restricts spreading of H3K27me3 around expressed genes. D) PRC1-mediated H2a119Ub is involved in recruitment of PRC2 at many gene promoters, which leads subsequent gene suppression.

Figure 2.. Interdependent changes in histone modifications, DNA methylation, chromatin compaction, 3D genomic structure, and their impact on gene expression in CRC.

A) Abnormal H3K27me3 spreading during differentiation causes repression of associated genes. B) Large scale loss of DNA methylation allows spreading of H3K27me3 that contributes to rearrangement of compacted chromatin. C) Abnormally high expression of noncoding RNAs such as the HOTAIR is involved in aberrant PRC2 recruitment and target gene suppression. D) Gain of DNA methylation at promoter associated CGIs is a common feature in CRC that leads to abnormal expression profile in cancer cells.

Figure 3.. Epigenetic changes functionally linked to IBD through control of immune cell differentiation, activation, and inflammatory response.

A) Treg cell-specific transcription factor FoxP3 directs Ezh2 and the PRC2 complex to specific genomic loci causing H3K27me3 deposition and repression of surrounding target genes. This epigenetic gene control is essential for immune suppression during inflammation. B) T cell differentiation and lineage determination is linked to cell-type-specific activation of H3K27me3 repressed genes in naïve T cell. Targeted action of H3K27 demethylase Kdm6b enables formation of appropriate gene expression patterns and production of Th1 or Th2 and Th17 cell types.