Epigenetics, DNA Organization, and Inflammatory Bowel Disease

Abstract

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal tract. The incidence of IBD is increasing, with more cases occurring in developed countries. Multiple factors such as genetics, environmental changes, gut microbiota, and immune abnormalities have been associated with development of IBD. In recent years, it has become increasingly apparent that epigenetic modifications of chromatin and the manner in which chromatin is organized in the nucleus are additionally important elements that can influence responses induced by the factors described above, and may therefore contribute to the onset and pathogenesis of IBD. Epigenetics and chromatin organization regulate diverse functions that include maintenance of homeostasis in the intestinal epithelium, the development and differentiation of immune cells, and modulation of responses generated by the immune system to defend against potential pathogens. Furthermore, changes in epigenetic chromatin marks and in chromatin organization have now been linked to differential gene expression in IBD patient cells. Although direct evidence for a role of histone modifications in IBD is currently very limited, in this review, we summarize the links between various epigenetic modifications, the proteins that catalyze or recognize these modifications, and the development or progression of IBD in human and experimental IBD. We also discuss how epigenetics influence the organization of DNA contacts to regulate gene expression and the implications this may have for diagnosing and treating IBD.

FIGURE 1.

The nucleosome is the basic packaging unit of chromatin. The nucleosome is composed of an octamer of histone proteins, comprising a hetero-tetramer of histones H3 and H4, surrounded by 2 hetero-dimers of histones H2A and H2B. DNA is wrapped approximately 1.7 times around the histone core. Lysine (K) residues present on the N-terminal tails of histones undergo several post-translational modifications such as addition of acetyl (Ac) and methyl (Me) groups. These histone modifications contribute to the epigenetic regulation of gene transcription.

FIGURE 2.

The 3-dimensional organization of chromatin plays an important role in regulating gene expression. A–B, Illustrations of different ways in which the formation of DNA loops mediated by genome organizing complexes (purple) can regulate gene expression. In A, a regulatory element (RE) that activates gene expression, such as an enhancer, interacts with the promoter of gene Y which, following binding of transcription factors, results in enhancement of transcription. In B, the RE confers a repressive activity, possibly by directing DNA methylation (yellow circles) of gene Y’s promoter, or by facilitating binding of chromatin remodeling proteins that promote repressive histone modifications (red hexagons). This represses transcription of gene Y.

FIGURE 3.

Histone modifications help to maintain homeostasis in the intestinal epithelium. Histone methylation induced by Polycomb repressive complexes are responsible for intestinal stem cell identity and regeneration following epithelial damage, as well as for proliferation of absorptive and secretory precursors in the transit amplifying (TA) compartments within the intestinal crypt. Histone acetylation and deacetylation play important roles in restricting differentiation of absorptive precursors while promoting differentiation of secretory cells. PRC, Polycomb repressive complex; HDAC, Histone deacetylase; TA, transit-amplifying.

FIGURE 4.

T cell differentiation and function within the intestinal lamina propria are regulated by histone modifications. A, JMJD3 H3K27me3 demethylase modulates the differentiation of T-cell subsets. The “?” sign refers to a conflicting study which shows that JMJD3 promotes Th17 differentiation (60). B, During intestinal inflammation, histone lysine methyltransferase G9A restricts TGF-beta-mediated differentiation of Th17 and Treg cells. C, Transcription factor Helios recruits histone deacetylases to suppress IL-2 expression in Tregs, leading to Treg anergy. D, Loss of mechanisms that regulate histone modifications can impact the severity of colitis. Loss of JMJD3 caused less severe colitis in mice, whereas depletion of G9A protects against severe colitis. Loss of Helios leads to increased IL-2 expression in Tregs and loss of anergy, in addition to more severe colitis in mice. Supporting references are in brackets. JMJD3-Jumonji domain-containing protein 3.