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

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. Transcriptional regulatory mechanisms have a dual role in specifying intestinal epithelial identity and enabling microbial responsiveness. In this Review, Rawls and colleagues describe what is currently known about the epigenetic patterning and transcription factors responsible for this duality. Key points Regional and cell identities in the intestinal epithelium of vertebrates are patterned through interactions between changes in the chromatin landscape and transcription factors. DNA methylation and accessible chromatin in intestinal epithelial cells are relatively stable in response to the gut microbiota. Histone modifications and transcription factor activity respond dynamically to microbial colonization. Transcription factors often have dual roles, to various degrees, in specifying intestinal epithelial identity and microbial responsiveness. Nuclear receptors seem to be key mediators of intestinal epithelial responses to the gut microbiota.