The actin depolymerizing factor, Destrin, serves as a negative feedback inhibitor of smooth muscle cell differentiation

Am J Physiol Heart Circ Physiol. 2021 Sep 24. doi: 10.1152/ajpheart.00142.2021. Online ahead of print.ABSTRACTWe have previously shown that several components of the RhoA signaling pathway control SMC phenotype by altering SRF-dependent gene expression. Because our genome wide analyses of chromatin structure and transcription factor binding suggested that the actin depolymerizing factor, DSTN, was regulated in a SMC-selective fashion, the goals of the current study were to identify the transcription mechanisms that control DSTN expression in SMC and to test whether it regulates SMC function. Immunohistochemical analyses revealed strong and at least partially SMC-selective expression of DSTN in many mouse tissues, a result consistent with human data from the GTEx consortium. We identified several regulatory regions that control DSTN expression including a SMC-selective enhancer that was activated by the MRTF/SRF, Notch/RBPJ, and SMAD transcription factors. Indeed, enhancer activity and endogenous DSTN expression were up-regulated by RhoA and TGF-β signaling and down-regulated by the Notch inhibitor, DAPT. We also showed that DSTN expression was decreased in vivo by carotid artery injury and in cultured SMC cells by PDGF-BB treatment. siRNA-mediated depletion of DSTN significantly enhanced MRTF-A nuclear localization and SMC differentiation marker gene expression; decreased SMC migration in scratch wound assays; and decreased SMC proliferation as measured by cell number and cy...
Source: American Journal of Physiology. Heart and Circulatory Physiology - Category: Physiology Authors: Source Type: research