An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm

Christian L. Lino Cardenas, Chase W. Kessinger, Yisha Cheng, Carolyn MacDonald, Thomas MacGillivray, Brian Ghoshhajra, Luai Huleihel, Saifar Nuri, Ashish S. Yeri, Farouc A. Jaffer, Naftali Kaminski, Patrick Ellinor, Neal L. Weintraub, Rajeev Malhotra, Eric M. Isselbacher, Mark E. Lindsay

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

Thoracic aortic aneurysm (TAA) has been associated with mutations affecting members of the TGF-β signaling pathway, or components and regulators of the vascular smooth muscle cell (VSMC) actomyosin cytoskeleton. Although both clinical groups present similar phenotypes, the existence of potential common mechanisms of pathogenesis remain obscure. Here we show that mutations affecting TGF-β signaling and VSMC cytoskeleton both lead to the formation of a ternary complex comprising the histone deacetylase HDAC9, the chromatin-remodeling enzyme BRG1, and the long noncoding RNA MALAT1. The HDAC9-MALAT1-BRG1 complex binds chromatin and represses contractile protein gene expression in association with gain of histone H3-lysine 27 trimethylation modifications. Disruption of Malat1 or Hdac9 restores contractile protein expression, improves aortic mural architecture, and inhibits experimental aneurysm growth. Thus, we highlight a shared epigenetic pathway responsible for VSMC dysfunction in both forms of TAA, with potential therapeutic implication for other known HDAC9-associated vascular diseases.

Original languageEnglish (US)
Article number1009
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Lino Cardenas, C. L., Kessinger, C. W., Cheng, Y., MacDonald, C., MacGillivray, T., Ghoshhajra, B., Huleihel, L., Nuri, S., Yeri, A. S., Jaffer, F. A., Kaminski, N., Ellinor, P., Weintraub, N. L., Malhotra, R., Isselbacher, E. M., & Lindsay, M. E. (2018). An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nature communications, 9(1), [1009]. https://doi.org/10.1038/s41467-018-03394-7