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.
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.
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The authors are grateful to members of the laboratory of J.F.R. for their helpful feedback on this manuscript. The authors were supported by a Pew Scholars Innovation Fund Award (J.F.R.) and NIH grants R01-DK081426, R24-DK110492, R01-DK093399, R01-DK113123, R24-OD016761, and P01-DK094779 (J.F.R.), F31-DK121392 (C.K.), and the UNC-CH Gastroenterology Research Training Program T32-DK07737 (J.K.H.).
The authors declare no competing interests.
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- Intestinal epithelial cells
(IECs). The cells that comprise the columnar epithelial layer that lines the lumen of the digestive tract from the anterior small intestine to the rectum, serving multiple functions including as a physical barrier and an absorptive tissue.
- Gut microbiota
The microorganisms that colonize the lumen and mucosal surfaces of the gastrointestinal tract.
- Intestinal cell type or lineage identity
The intestinal epithelium comprises many different specialized types of cells (for example, absorptive enterocytes, enteroendocrine cells, goblet cells) that are specified partly through distinct gene expression programmes.
The complex consisting of chromosomal DNA and associated protein and RNA within the nucleus.
- Inflammatory bowel disease
(IBD). Conditions characterized by chronic inflammation of the intestine, most commonly ulcerative colitis and Crohn’s disease.
- Transcription factors
Proteins that regulate transcription (gene expression), typically by binding to specific DNA sequences.
- Anterior–posterior axis of the intestine
Differences in the physiological function and underlying cellular composition and gene expression patterns along the anterior–posterior axis of the gastrointestinal tract. This regionality is typically categorized into the major regions of the gastrointestinal tract (for example, duodenum, jejunum, ileum, colon, etc.).
- Intestinal stem cells
(ISCs). Cells in the intestinal epithelium that undergo self-renewal and also give rise to all of the different intestinal epithelial cell types. They are stereotypically located at the base of intestinal crypts or rugae.
- Secretory cells
A major IEC lineage with diverse functions mediated partially through secretion of products into the lumen. The secretory cell lineage includes Paneth cells, tuft cells, goblet cells and enteroendocrine cells.
- Absorptive cell
A major IEC lineage that gives rise to absorptive enterocytes, the most abundant cell type in the intestine, which are also responsible for absorption of nutrients and other cargoes.
- Lysosome-rich enterocytes
(LREs). Specialized absorptive cell type found in the intestines characterized by a large lysosomal vacuole and involved in cellular digestion of macromolecular cargoes. These cells develop in diverse vertebrate species but are often overlooked in mammals because they are only present during the ‘suckling’ or perinatal developmental stages.
- Lineage-specific transcription factors
Transcription factors that function early on in the differentiation of a cell lineage or tissue that have a role in shaping the chromatin landscape, setting the stage for further transcription factor binding and lineage specification. Lineage-specifying transcription factors are functionally similar to pioneer transcription factors, but unlike pioneer transcription factors they have not definitively been shown to directly bind to condensed chromatin.
- DNA methylation
The addition of methyl groups on DNA bases that serves as an additional layer of genetic information that can impact the expression of genes. Typically, methylation of a gene promoter results in suppression of that gene’s transcription.
- Chromatin accessibility
The degree to which regions of chromatin DNA are available for transcription factor binding or other regulatory processes. Typically, chromatin accessibility is low due to nucleosome occupancy and can be modulated by post-translational modification of histone tails. This term is used interchangeably with chromatin openness.
- Histone modifications
Post-translational modifications on the tails of histone proteins that can influence regional gene expression and other physical and enzymatic genome utilization dynamics.
- Cis-regulatory DNA regions
(CRRs). Typically non-coding regions of the genome often involved in modulating the transcription of a nearby gene. This term is used interchangeably with cis-regulatory element (CRE).
Structural unit of DNA organization in the nucleus, consisting of DNA wrapped around a complex of eight histone proteins.
- Short-chain fatty acids
(SCFAs). Short-chain fatty acids are products of microbial fermentation of non-digestible dietary fibre and protein, and a main source of energy for epithelial cells in the colon.
- Bile acid
Cholesterol-derived acids that are secreted from the gallbladder into the small intestine. They assist in emulsification of dietary fats, act as ligands for multiple host receptors and transcription factors and can be chemically modified by the intestinal microbiota.
- Nuclear receptor
A family of ligand-binding transcription factors with important roles in intestinal epithelial cells that regulate the expression of genes associated with diverse processes from development to metabolism.
Chemicals that are foreign to the body.
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Heppert, J.K., Davison, J.M., Kelly, C. et al. Transcriptional programmes underlying cellular identity and microbial responsiveness in the intestinal epithelium. Nat Rev Gastroenterol Hepatol (2020). https://doi.org/10.1038/s41575-020-00357-6