Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity.

EMBO Reports
Masahiro KimuraKoh Ono

Abstract

The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes-associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of YAP/TEAD-mediated gene expressions involved in vascular pathophysiology remains to be elucidated. Here, we identified Homeobox A4 (HOXA4) as a potent repressor of YAP/TEAD transcriptional activity using lentiviral shRNA screen. Mechanistically, HOXA4 interacts with TEADs and attenuates YAP/TEAD-mediated transcription by competing with YAP for TEAD binding. We also clarified that the expression of HOXA4 is relatively abundant in the vasculature, especially in VSMCs. In vitro experiments in human VSMCs showed HOXA4 maintains the differentiation state of VSMCs via inhibition of YAP/TEAD-induced phenotypic switching. We generated Hoxa4-deficient mice and confirmed the downregulation of smooth muscle-specific contractile genes and the exacerbation of vascular remodeling after carotid artery ligation in vivo. Our results demonstrate that HO...Continue Reading

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Citations

Jun 16, 2021·Development·Laura CurreyMichael Piper
Jun 27, 2021·The FEBS Journal·Jiahong XieHongfeng Jiang
Apr 24, 2021·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ekaterina MostovenkoAndrew K Ottens
Sep 14, 2021·Molecular and Cellular Biology·Elizabeth L CastleJennifer A Corcoran

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Methods Mentioned

BETA
PCR
immunoprecipitation
co‐IP
ChIP
Assay
FACS

Software Mentioned

ImageJ64
GraphPad Prism
Barcode Deconvolution
Cellecta

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