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Transcriptional programmes underlying cellular identity and microbial responsiveness in the intestinal epithelium.

ABSTRACT: The intestinal epithelium serves the unique and critical function of harvesting dietary nutrients, while simultaneously acting as a cellular barrier separating tissues from the luminal environment and gut microbial ecosystem. Two salient features of the intestinal epithelium enable it to perform these complex functions. First, cells within the intestinal epithelium achieve a wide range of specialized identities, including different cell types and distinct anterior-posterior patterning along the intestine. Second, intestinal epithelial cells are sensitive and responsive to the dynamic milieu of dietary nutrients, xenobiotics and microorganisms encountered in the intestinal luminal environment. These diverse identities and responsiveness of intestinal epithelial cells are achieved in part through the differential transcription of genes encoded in their shared genome. Here, we review insights from mice and other vertebrate models into the transcriptional regulatory mechanisms underlying intestinal epithelial identity and microbial responsiveness, including DNA methylation, chromatin accessibility, histone modifications and transcription factors. These studies are revealing that most transcription factors involved in intestinal epithelial identity also respond to changes in the microbiota, raising both opportunities and challenges to discern the underlying integrative transcriptional regulatory networks.

SUBMITTER: Heppert JK

PROVIDER: S-EPMC7997278 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & aimsThe intestine constantly interprets and adapts to complex combinations of dietary and microbial stimuli. However, the transcriptional strategies by which the intestinal epithelium integrates these coincident sources of information remain unresolved. We recently found that microbiota colonization suppresses epithelial activity of hepatocyte nuclear factor 4 nuclear receptor transcription factors, but their integrative regulation was unknown.MethodsWe compared adult mice reared germ-free or conventionalized with a microbiota either fed normally or after a single high-fat meal. Preparations of unsorted jejunal intestinal epithelial cells were queried using lipidomics and genome-wide assays for RNA sequencing and ChIP sequencing for the activating histone mark H3K27ac and hepatocyte nuclear factor 4 alpha.ResultsAnalysis of lipid classes, genes, and regulatory regions identified distinct nutritional and microbial responses but also simultaneous influence of both stimuli. H3K27ac sites preferentially increased by high-fat meal in the presence of microbes neighbor lipid anabolism and proliferation genes, were previously identified intestinal stem cell regulatory regions, and were not hepatocyte nuclear factor 4 alpha targets. In contrast, H3K27ac sites preferentially increased by high-fat meal in the absence of microbes neighbor targets of the energy homeostasis regulator peroxisome proliferator activated receptor alpha, neighbored fatty acid oxidation genes, were previously identified enterocyte regulatory regions, and were hepatocyte factor 4 alpha bound.ConclusionsHepatocyte factor 4 alpha supports a differentiated enterocyte and fatty acid oxidation program in germ-free mice, and that suppression of hepatocyte factor 4 alpha by the combination of microbes and high-fat meal may result in preferential activation of intestinal epithelial cell proliferation programs. This identifies potential transcriptional mechanisms for intestinal adaptation to multiple signals and how microbiota may modulate intestinal lipid absorption, epithelial cell renewal, and systemic energy balance.

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Transcriptional programmes underlying cellular identity and microbial responsiveness in the intestinal epithelium.

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