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Nat Genet. 2019 May;51(5):777-785. doi: 10.1038/s41588-019-0384-0. Epub 2019 Apr 15.

A reinforcing HNF4-SMAD4 feed-forward module stabilizes enterocyte identity.

Author information

1
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
2
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
3
Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA.
4
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA. verzi@biology.rutgers.edu.
5
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. verzi@biology.rutgers.edu.

Abstract

BMP/SMAD signaling is a crucial regulator of intestinal differentiation1-4. 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 plasticity5.

PMID:
30988513
DOI:
10.1038/s41588-019-0384-0

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