Logo image
Back
Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz
Journal article   Open access   Peer reviewed

Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz

Dakota L Jones, Grey F Hallström, Xi Jiang, Ryan C Locke, Mary Kate Evans, Edward D Bonnevie, Anjana Srikumar, Thomas P Leahy, Madhura P Nijsure, Joel D Boerckel, …
Proceedings of the National Academy of Sciences - PNAS, Vol.120(22), p.e2211947120
05/30/2023
DOI: 10.1073/pnas.2211947120
PMCID: PMC10235980
PMID: 37216538
url
https://doi.org/10.1073/pnas.2211947120View
Published (Version of record) Open Access

Abstract

Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function are not well understood. Here, we show using a model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs, resulting in subsequent weakening of the tendon. In vitro studies using paired ATAC/RNAseq demonstrate that the loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Concordantly, the depletion of Yap/Taz elevates matrix catabolic expression. Conversely, overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. The overexpression of Yap not only prevents the induction of this broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanoepigenetic signals regulate tendon cell function through a Yap/Taz axis.
 Chromatin - genetics Chromatin - metabolism Extracellular Matrix - genetics Extracellular Matrix - metabolism Homeostasis Signal Transduction - genetics Trans-Activators - metabolism Transcription Factors - genetics Transcription Factors - metabolism Transcriptional Coactivator with PDZ-Binding Motif Proteins - genetics Transcriptional Coactivator with PDZ-Binding Motif Proteins - metabolism YAP-Signaling Proteins - genetics YAP-Signaling Proteins - metabolism

Details

Metrics

7 Record Views
46 Times Cited - Web of Science
Logo image