The nuclear receptor HNF4 drives a brush border gene program conserved across murine intestine, kidney, and embryonic yolk sac

Lei Chen (), Shirley Luo, Abigail Dupre, Roshan P. Vasoya, Aditya Parthasarathy, Rohit Aita, Raj Malhotra, Joseph Hur, Natalie H. Toke, Eric Chiles, Min Yang, Weihuan Cao, Juan Flores, Christopher E. Ellison, Nan Gao, Amrik Sahota, Xiaoyang Su, Edward M. Bonder and Michael P. Verzi ()
Additional contact information
Lei Chen: Rutgers University
Shirley Luo: Rutgers University
Abigail Dupre: Rutgers University
Roshan P. Vasoya: Rutgers University
Aditya Parthasarathy: Rutgers University
Rohit Aita: Rutgers University
Raj Malhotra: Rutgers University
Joseph Hur: Rutgers University
Natalie H. Toke: Rutgers University
Eric Chiles: Rutgers Cancer Institute of New Jersey, Rutgers University
Min Yang: Rutgers University
Weihuan Cao: Rutgers University
Juan Flores: Rutgers University
Christopher E. Ellison: Rutgers University
Nan Gao: Rutgers University
Amrik Sahota: Rutgers University
Xiaoyang Su: Rutgers Cancer Institute of New Jersey, Rutgers University
Edward M. Bonder: Rutgers University
Michael P. Verzi: Rutgers University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract The brush border is comprised of microvilli surface protrusions on the apical surface of epithelia. This specialized structure greatly increases absorptive surface area and plays crucial roles in human health. However, transcriptional regulatory networks controlling brush border genes are not fully understood. Here, we identify that hepatocyte nuclear factor 4 (HNF4) transcription factor is a conserved and important regulator of brush border gene program in multiple organs, such as intestine, kidney and yolk sac. Compromised brush border gene signatures and impaired transport were observed in these tissues upon HNF4 loss. By ChIP-seq, we find HNF4 binds and activates brush border genes in the intestine and kidney. H3K4me3 HiChIP-seq identifies that HNF4 loss results in impaired chromatin looping between enhancers and promoters at gene loci of brush border genes, and instead enhanced chromatin looping at gene loci of stress fiber genes in the intestine. This study provides comprehensive transcriptional regulatory mechanisms and a functional demonstration of a critical role for HNF4 in brush border gene regulation across multiple murine epithelial tissues.

Date: 2021
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DOI: 10.1038/s41467-021-22761-5

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