Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity.
Hippo signaling
homeobox genes
phenotypic switching
vascular remodeling
Journal
EMBO reports
ISSN: 1469-3178
Titre abrégé: EMBO Rep
Pays: England
ID NLM: 100963049
Informations de publication
Date de publication:
03 04 2020
03 04 2020
Historique:
received:
01
05
2019
revised:
31
01
2020
accepted:
12
02
2020
pubmed:
10
3
2020
medline:
28
4
2021
entrez:
10
3
2020
Statut:
ppublish
Résumé
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 HOXA4 is a repressor of VSMC phenotypic switching by inhibiting YAP/TEAD-mediated transcription.
Identifiants
pubmed: 32147946
doi: 10.15252/embr.201948389
pmc: PMC7132199
doi:
Substances chimiques
Homeodomain Proteins
0
Hoxa4 protein, mouse
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e48389Subventions
Organisme : MEXT|Japan Society for the Promotion of Science (JSPS)
ID : 17H04177
Pays : International
Organisme : MEXT|Japan Society for the Promotion of Science (JSPS)
ID : 17H05599
Pays : International
Organisme : MEXT|Japan Society for the Promotion of Science (JSPS)
ID : 17K19590
Pays : International
Organisme : MEXT|Japan Society for the Promotion of Science (JSPS)
ID : 17K09860
Pays : International
Organisme : MEXT|Japan Society for the Promotion of Science (JSPS)
ID : JP1605297
Pays : International
Organisme : Takeda Science Foundation
Pays : International
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
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