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A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity
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A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity
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Journal Article
A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity
2019
Overview
BMP/SMAD signaling is a crucial regulator of intestinal differentiation
1
–
4
. However, the molecular underpinnings of the BMP pathway in this context are unknown. Here, we characterize the mechanism by which BMP/SMAD signaling drives enterocyte differentiation. We establish that the transcription factor HNF4A acts redundantly with an intestine-restricted HNF4 paralog, HNF4G, to activate enhancer chromatin and upregulate the majority of transcripts enriched in the differentiated epithelium; cells fail to differentiate on double knockout of both HNF4 paralogs. Furthermore, we show that SMAD4 and HNF4 function via a reinforcing feed-forward loop, activating each other’s expression and co-binding to regulatory elements of differentiation genes. This feed-forward regulatory module promotes and stabilizes enterocyte cell identity; disruption of the HNF4–SMAD4 module results in loss of enterocyte fate in favor of progenitor and secretory cell lineages. This intersection of signaling and transcriptional control provides a framework to understand regenerative tissue homeostasis, particularly in tissues with inherent cellular plasticity
5
.
The authors show that the transcription factors HNF4A and HNF4G regulate the transcriptome of the intestinal epithelium. HNF4 factors cooperate with BMP/SMAD signaling to promote enterocyte identity.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 13/31
/ 13/51
/ 14/19
/ 14/63
/ 38/39
/ 38/77
/ 38/90
/ 38/91
/ 45/15
/ 64/110
/ 64/60
/ 82/29
/ Animal Genetics and Genomics
/ Animals
/ Biomedical and Life Sciences
/ Cell Differentiation - genetics
/ Cell Differentiation - physiology
/ DNA
/ Genomes
/ Genomics
/ Hepatocyte Nuclear Factor 4 - deficiency
/ Hepatocyte Nuclear Factor 4 - genetics
/ Hepatocyte Nuclear Factor 4 - metabolism
/ Humans
/ Letter
/ Mice
/ Modules
/ Ontology
