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

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere202007152
JournalJournal of Cell Biology
Volume220
Issue number5
DOIs
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Cell Biology

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