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

Lei Chen, Natalie H. Toke, Shirley Luo, Roshan P. Vasoya, Robert L. Fullem, Aditya Parthasarathy, Ansu O. Perekatt, Michael P. Verzi

Research output: Contribution to journalLetter

9 Scopus citations


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 .

Original languageEnglish (US)
Pages (from-to)777-785
Number of pages9
JournalNature genetics
Issue number5
StatePublished - May 1 2019

All Science Journal Classification (ASJC) codes

  • Genetics

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    Chen, L., Toke, N. H., Luo, S., Vasoya, R. P., Fullem, R. L., Parthasarathy, A., Perekatt, A. O., & Verzi, M. P. (2019). A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity. Nature genetics, 51(5), 777-785. https://doi.org/10.1038/s41588-019-0384-0