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Development. 2019 Aug 6;146(19). pii: dev179432. doi: 10.1242/dev.179432.

HNF4 factors control chromatin accessibility and are redundantly required for maturation of the fetal intestine.

Author information

1
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA.
2
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
3
Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
4
Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA.
6
Center for Organogenesis, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
7
Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ 08854, USA verzi@biology.rutgers.edu.

Abstract

As embryos mature, cells undergo remarkable transitions that are accompanied by shifts in transcription factor regulatory networks. Mechanisms driving developmental transitions are incompletely understood. The embryonic intestine transitions from a rapidly proliferating tube with pseudostratified epithelium prior to murine embryonic day (E) 14.5 to an exquisitely folded columnar epithelium in fetal stages. We sought to identify factors driving mouse fetal intestinal maturation by mining chromatin accessibility data for transcription factor motifs. ATAC-seq accessible regions shift during tissue maturation, with CDX2 transcription factor motifs abundant at chromatin-accessible regions of the embryo. Hepatocyte nuclear factor 4 (HNF4) transcription factor motifs are the most abundant in the fetal stages (>E16.5). Genetic inactivation of Hnf4a and its paralog Hnf4g revealed that HNF4 factors are redundantly required for fetal maturation. CDX2 binds to and activates Hnf4 gene loci to elevate HNF4 expression at fetal stages. HNF4 and CDX2 transcription factors then occupy shared genomic regulatory sites to promote chromatin accessibility and gene expression in the maturing intestine. Thus, HNF4 paralogs are key components of an intestinal transcription factor network shift during the embryonic to fetal transition.

KEYWORDS:

Chromatin; Developing intestine; HNF4 transcription factors; Maturation

PMID:
31345929
DOI:
10.1242/dev.179432

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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