Abstract

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
Volume51
Issue number5
DOIs
StatePublished - May 1 2019

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Enterocytes
Cell Lineage
Chromatin
Intestines
Homeostasis
Transcription Factors
Up-Regulation
Stem Cells
Epithelium
Genes

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

@article{2078f3573429446da2e0a1a6b3d91161,
title = "A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity",
abstract = "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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A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity. / Verzi, Michael P.

In: Nature genetics, Vol. 51, No. 5, 01.05.2019, p. 777-785.

Research output: Contribution to journalLetter

TY - JOUR

T1 - A reinforcing HNF4–SMAD4 feed-forward module stabilizes enterocyte identity

AU - Verzi, Michael P.

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 .

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U2 - https://doi.org/10.1038/s41588-019-0384-0

DO - https://doi.org/10.1038/s41588-019-0384-0

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VL - 51

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EP - 785

JO - Nature Genetics

JF - Nature Genetics

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