ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation

Dakota L. Jones; Jeffrey A. Meridew; Patrick A. Link; Merrick T. Ducharme; Katherine L. Lydon; Kyoung M. Choi; Nunzia Caporarello; Qi Tan; Ana Maria Diaz Espinosa; Yuning Xiong; Jeong-Heon Lee; Zhenqing Ye; Huihuang Yan; Tamas Ordog; Giovanni Ligresti; Xaralabos Varelas; Daniel J. Tschumperlin

doi:10.1083/jcb.202007152

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ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation

Journal article

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ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation

Dakota L. Jones, Jeffrey A. Meridew, Patrick A. Link, Merrick T. Ducharme, Katherine L. Lydon, Kyoung M. Choi, Nunzia Caporarello, Qi Tan, Ana Maria Diaz Espinosa, Yuning Xiong, …

The Journal of cell biology, Vol.220(5), e202007152

05/03/2021

DOI: 10.1083/jcb.202007152

PMCID: PMC7918622

PMID: 33625469

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Abstract

Jones et al. determine the role of matrix stiffness in regulating chromatin accessibility in freshly isolated lung fibroblasts. They identify ZNF416 as a key transcriptional regulator controlling fibroblast activation by the mechanical environment with relevance to wound healing and fibrosis. Matrix stiffness is a central regulator of fibroblast function. However, the transcriptional mechanisms linking matrix stiffness to changes in fibroblast phenotype are incompletely understood. Here, we evaluated the effect of matrix stiffness on genome-wide chromatin accessibility in freshly isolated lung fibroblasts using ATAC-seq. We found higher matrix stiffness profoundly increased global chromatin accessibility relative to lower matrix stiffness, and these alterations were in close genomic proximity to known profibrotic gene programs. Motif analysis of these regulated genomic loci identified ZNF416 as a putative mediator of fibroblast stiffness responses. Genome occupancy analysis using ChIP-seq confirmed that ZNF416 occupies a broad range of genes implicated in fibroblast activation and tissue fibrosis, with relatively little overlap in genomic occupancy with other mechanoresponsive and profibrotic transcriptional regulators. Using loss- and gain-of-function studies, we demonstrated that ZNF416 plays a critical role in fibroblast proliferation, extracellular matrix synthesis, and contractile function. Together, these observations identify ZNF416 as novel mechano-activated transcriptional regulator of fibroblast biology.

Cytoskeleton

Disease

Physiology

Chromatin or Epigenetics

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Title: Subtitle: ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation
Creators: Dakota L. Jones - Mayo Clinic
Jeffrey A. Meridew - Mayo Clinic
Patrick A. Link - Mayo Clinic
Merrick T. Ducharme - Mayo Clinic
Katherine L. Lydon - Mayo Clinic
Kyoung M. Choi - Mayo Clinic
Nunzia Caporarello - Mayo Clinic
Qi Tan - Mayo Clinic
Ana Maria Diaz Espinosa - Mayo Clinic
Yuning Xiong - Mayo Clinic in Arizona
Jeong-Heon Lee - Mayo Clinic
Zhenqing Ye - Mayo Clinic in Florida
Huihuang Yan - Mayo Clinic in Florida
Tamas Ordog - Mayo Clinic
Giovanni Ligresti - Boston University
Xaralabos Varelas - Boston University
Daniel J. Tschumperlin - Mayo Clinic
Resource Type: Journal article
Publication Details: The Journal of cell biology, Vol.220(5), e202007152
DOI: 10.1083/jcb.202007152
PMID: 33625469
PMCID: PMC7918622
NLM abbreviation: J Cell Biol
ISSN: 0021-9525
eISSN: 1540-8140
Publisher: Rockefeller University Press
Grant note: T32 HL105355; DK058185; DK084567; HL142596; HL124392; HL092961; HL133320 / ;
Alternative title: ZNF416 regulates fibroblast mechanoactivation
Language: English
Date published: 05/03/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Anatomy and Cell Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984948145402771

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