期刊
NATURE GENETICS
卷 51, 期 5, 页码 777-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-019-0384-0
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资金
- National Institutes of Health (NIH) [R01CA190558]
- Intestinal Stem Cell Consortium - National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the NIH [U01 DK103141]
- National Institute of Allergy and Infectious Diseases (NIAID) of the NIH [U01 DK103141]
- New Jersey Commission on Cancer Research [DFHS18PPC051]
- MacMillan Summer Undergraduate Research Fellowships
- Rutgers Cancer Institute of New Jersey [P30CA072720]
- next-generation sequencing services of RUCDR
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).
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