Mechanoepigenetic regulation of extracellular matrix homeostasis via Yap and Taz

细胞生物学 染色质 分解代谢 细胞外基质 生物 基因表达 基因表达调控 平衡 细胞命运测定 功能(生物学) 基因 转录因子 遗传学 生物化学 新陈代谢
作者
Dakota L. Jones,Grey F. Hallström,Xi Jiang,Ryan C. Locke,Mary Kate Evans,Edward D. Bonnevie,Anjana Srikumar,Thomas Leahy,Madhura P. Nijsure,Joel D. Boerckel,Robert L. Mauck,Nathaniel A. Dyment
出处
期刊:Proceedings of the National Academy of Sciences of the United States of America [Proceedings of the National Academy of Sciences]
卷期号:120 (22) 被引量:2
标识
DOI:10.1073/pnas.2211947120
摘要

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.
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