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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites / genetics
  • Caco-2 Cells
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Enhancer Elements, Genetic
  • Enterocytes / cytology*
  • Enterocytes / metabolism*
  • Hepatocyte Nuclear Factor 4 / deficiency
  • Hepatocyte Nuclear Factor 4 / genetics
  • Hepatocyte Nuclear Factor 4 / metabolism*
  • Humans
  • Mice
  • Mice, Knockout
  • Signal Transduction
  • Smad4 Protein / deficiency
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism*


  • HNF4A protein, human
  • HNF4G protein, human
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Hnf4g protein, mouse
  • SMAD4 protein, human
  • Smad4 Protein
  • Smad4 protein, mouse