Impact of the gut microbiota on enhancer accessibility in gut intraepithelial lymphocytes

Abstract

The gut microbiota impacts many aspects of host biology including immune function. One hypothesis is that microbial communities induce epigenetic changes with accompanying alterations in chromatin accessibility, providing a mechanism that allows a community to have sustained host effects even in the face of its structural or functional variation. We used Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) to define chromatin accessibility in predicted enhancer regions of intestinal αβ + and γδ + intraepithelial lymphocytes purified from germ-free mice, their conventionally raised (CONV-R) counterparts, and mice reared germ free and then colonized with CONV-R gut microbiota at the end of the suckling-weaning transition. Characterizing genes adjacent to traditional enhancers and super-enhancers revealed signaling networks, metabolic pathways, and enhancer-associated transcription factors affected by the microbiota. Our results support the notion that epigenetic modifications help define microbial community-affiliated functional features of host immune cell lineages.gut microbiota-immune cell interactions | ATAC-seq | enhancers of gut intraepithelial lymphocytes | transcription factors | gnotobiotic mice

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…We provide the genomic addresses of hundreds of microbiota-regulated enhancers as well as the genes associated with these enhancers and HNF4A binding sites. Similar to other findings in intra-epithelial lymphocytes (Semenkovich et al 2016), our work demonstrates a clear microbial contribution to the modification of the histone landscape in IECs and provides another important layer of regulation that orchestrates microbiota regulation of host genes involved in intestinal physiology and human disease. We were also able to establish a link between microbiota-regulated genes and enhancers and NR binding sites.…”

Microbial dysbiosis-induced obesity: role of gut microbiota in homoeostasis of energy metabolism

“…The DNA methylation changes can be reproduced by faecal transplantation (78) . Chromatin structure in intestinal intraepithelial lymphocytes (79) and several host tissues is also modified by gut microbiota in a diet-dependent manner (80) . The result is alterations in gene transcription/expression and host physiology (80) .…”

“…An offspring could be a product of the combination of the dietary patterns of both the offspring and mother. Prenatal exposure to adverse (obesogenic) microbiota-metabolic environment may increase the offspring's susceptibility to obesity in postnatal life (79) . This has been demonstrated by examining maternal mechanisms regulating developmental programming of offspring obesity in rats (31,86,87) .…”

Metabolic programming of the epigenome: host and gut microbial metabolite interactions with host chromatin

“…Priming of NK cells in the innate immune system has also been shown to be partially affected by differential histone H3K4me3 enrichment at transcriptional start sites of microbiota-mediated inflammatory response genes, and treatment of conventionally raised (ConvR) mice with antibiotics erased H3K4me3 at these genes (181). Differences in chromatin accessibility at enhancers in GF mice relative to their ConvR counterparts have also been identified in purified intraepithelial lymphocytes (IEL), revealing transcription factor circuits that are differentially regulated in GF and ConvR mice (182). Enhancers in IEL populations also stratify by their history of microbial exposure, where IEL enhancers from GF mice clustered separately from those in ConvR mice, which were colonized at birth, and from IELs in conventionalized mice (ConvD), which were colonized at 3 weeks of age (182).…”

“…Differences in chromatin accessibility at enhancers in GF mice relative to their ConvR counterparts have also been identified in purified intraepithelial lymphocytes (IEL), revealing transcription factor circuits that are differentially regulated in GF and ConvR mice (182). Enhancers in IEL populations also stratify by their history of microbial exposure, where IEL enhancers from GF mice clustered separately from those in ConvR mice, which were colonized at birth, and from IELs in conventionalized mice (ConvD), which were colonized at 3 weeks of age (182). Collectively, these studies suggest that the gut microbiota signals to innate and adaptive host defense systems via mechanisms that are at least partly tuned by chromatin responses.…”