TY - JOUR
T1 - A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity
AU - Chen, Lei
AU - Toke, Natalie H.
AU - Luo, Shirley
AU - Vasoya, Roshan P.
AU - Fullem, Robert L.
AU - Parthasarathy, Aditya
AU - Perekatt, Ansu O.
AU - Verzi, Michael P.
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/5/1
Y1 - 2019/5/1
N2 - 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 .
AB - 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 .
UR - http://www.scopus.com/inward/record.url?scp=85064529425&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85064529425&partnerID=8YFLogxK
U2 - 10.1038/s41588-019-0384-0
DO - 10.1038/s41588-019-0384-0
M3 - Letter
C2 - 30988513
AN - SCOPUS:85064529425
SN - 1061-4036
VL - 51
SP - 777
EP - 785
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -