| First Author | Chen L | Year | 2019 |
| Journal | Nat Genet | Volume | 51 |
| Issue | 5 | Pages | 777-785 |
| PubMed ID | 30988513 | Mgi Jnum | J:282638 |
| Mgi Id | MGI:6381257 | Doi | 10.1038/s41588-019-0384-0 |
| Citation | Chen L, et al. (2019) A reinforcing HNF4-SMAD4 feed-forward module stabilizes enterocyte identity. Nat Genet 51(5):777-785 |
| abstractText | 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). |
