The Methyl-CpG-Binding Protein Mbd2 Regulates Susceptibility to Experimental Colitis via Control of CD11c+ Cells and Colonic Epithelium

Abstract

Methyl-CpG-binding domain-2 (Mbd2) acts as an epigenetic regulator of gene expression, by linking DNA methylation to repressive chromatin structure. Although Mbd2 is widely expressed in gastrointestinal immune cells and is implicated in regulating intestinal cancer, anti-helminth responses and colonic inflammation, the Mbd2expressing cell types that control these responses are incompletely defined. Indeed, epigenetic control of gene expression in cells that regulate intestinal immunity is generally poorly understood, even though such mechanisms may explain the inability of standard genetic approaches to pinpoint the causes of conditions like inflammatory bowel disease. In this study we demonstrate a vital role for Mbd2 in regulating murine colonic inflammation. Mbd2 −/− mice displayed dramatically worse pathology than wild type controls during dextran sulfate sodium (DSS) induced colitis, with increased inflammatory (IL-1β +) monocytes. Profiling of mRNA from innate immune and epithelial cell (EC) populations suggested that Mbd2 suppresses inflammation and pathology via control of innate-epithelial cell crosstalk and T cell recruitment. Consequently, restriction of Mbd2 deficiency to CD11c + dendritic cells and macrophages, or to ECs, resulted in increased DSS colitis severity. Our identification of this dual role for Mbd2 in regulating the inflammatory capacity of both CD11c + cells and ECs highlights how epigenetic control mechanisms may limit intestinal inflammatory responses.

Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts

“…Interestingly therefore, the suppression of DC maturation, particularly in terms of TLR signalling, by total excretory-secretory products released by the parasitic trematode worm Fasciola gigantica (FgESPs) has recently been shown to be associated with changes in the methylome and transcriptome reprogramming [ 59 ]. Moreover, the methyl-CpG-binding protein, Mbd2, that acts to coordinate chromatin accessibility and hence, reprogramming of gene expression in response to DNA methylation, is key to the ability of DCs to drive Th2 responses to helminths and allergy [ 60 ] and also plays a role in CD11c + DC/monocyte-epithelial cell crosstalk in gut inflammation [ 61 ].…”

ES-62 suppression of arthritis reflects epigenetic rewiring of synovial fibroblasts to a joint-protective phenotype

“…Interestingly therefore, the suppression of DC maturation (buffalo cells), particularly in terms of TLR signalling, by excretory-secretory products released by the parasitic trematode worm Fasciola gigantica (FgESPs) has recently been shown to be associated with changes in the methylome and transcriptome reprogramming 96 . Moreover, the methyl-CpG-binding protein, Mbd2, that acts to coordinate chromatin accessibility and hence, reprogramming of gene expression in response to DNA methylation, is key to the ability of DCs to drive Th2 responses to helminths and allergy 97 and also plays a role in CD11c+ DC/monocyte-epithelial cell crosstalk in gut inflammation 98 . Although, exposure to ES-62 does not substantially impact on the methylation profile of Mbd2 in CIA-SFs, it results in TSS hypermethylation of Mbd3l2, a homologous protein that can also interact with components of the NuRD complex but to antagonize Mbd2-mediated methylation silencing 99, 100 , an inverse signature to that of naïve and CIA-SFs (hypomethylated).…”

GRaNIE and GRaNPA: Inference and evaluation of enhancer-mediated gene regulatory networks applied to study macrophages

“…S12 ). Less is known about MBD2 in macrophages, although it has been linked to intestinal inflammation in mice [44] and MBD2 deficiency has been associated with repressing the M2 macrophage programme in pulmonary fibrosis [45]. When we assessed the expression change upon infection with Salmonella for the genes in the IRF8 and MBD2 regulons, we observed that the IRF8 regulon is generally up-regulated upon infection, whereas the MBD2 regulon is mostly down-regulated ( Fig.…”

“…1I), which is in line with the typically scale-free structure of GRNs (32). The most connected TFs differ between the infected and the naive eGRN and include many well-established macrophage TFs such as IRF8, NFkB2, and RELB (33,34) and also less well established TFs such as MBD2, FOSL1 and NRF1, which have been implicated in macrophage biology in more recent studies in mice provide evidence for a role of MBD2, NRF1 FOSL1 in macrophages (35–37).…”