ZNF416 is a pivotal transcriptional regulator of fibroblast mechanoactivation
Autor: | Yuning Xiong, Patrick A. Link, Zhenqing Ye, Qi Tan, Nunzia Caporarello, Jeffrey A. Meridew, Merrick T. Ducharme, Dakota L. Jones, Giovanni Ligresti, Xaralabos Varelas, Huihuang Yan, Daniel J. Tschumperlin, Jeong Heon Lee, Tamas Ordog, Kyoung Moo Choi, Ana Espinosa, Katherine L. Lydon |
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Rok vydání: | 2021 |
Předmět: |
Chromatin or Epigenetics
Transcription Genetic Physiology Regulator Mice Transgenic Matrix (biology) Biology Extracellular matrix Mice 03 medical and health sciences 0302 clinical medicine Mediator Report medicine Transcriptional regulation Animals Disease Fibroblast Lung Cytoskeleton Cells Cultured Cell Proliferation 030304 developmental biology 0303 health sciences Genome technology industry and agriculture Cell Biology Fibroblasts equipment and supplies Fibrosis Phenotype Chromatin Extracellular Matrix Cell biology medicine.anatomical_structure Gene Expression Regulation 030217 neurology & neurosurgery |
Zdroj: | The Journal of Cell Biology |
ISSN: | 1540-8140 0021-9525 |
DOI: | 10.1083/jcb.202007152 |
Popis: | 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. |
Databáze: | OpenAIRE |
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