TY - JOUR
T1 - ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation
AU - Jones, Dakota L.
AU - Meridew, Jeffrey A.
AU - Link, Patrick A.
AU - Ducharme, Merrick T.
AU - Lydon, Katherine L.
AU - Choi, Kyoung M.
AU - Caporarello, Nunzia
AU - Tan, Qi
AU - Espinosa, Ana Maria Diaz
AU - Xiong, Yuning
AU - Lee, Jeong Heon
AU - Ye, Zhenqing
AU - Yan, Huihuang
AU - Ordog, Tamas
AU - Ligresti, Giovanni
AU - Varelas, Xaralabos
AU - Tschumperlin, Daniel J.
N1 - Publisher Copyright:
© 2021 Jones et al.
PY - 2021/2
Y1 - 2021/2
N2 - 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.
AB - 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.
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U2 - 10.1083/JCB.202007152
DO - 10.1083/JCB.202007152
M3 - Article
C2 - 33625469
AN - SCOPUS:85102322077
SN - 0021-9525
VL - 220
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 5
M1 - e202007152
ER -