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 Lee Weintraub, Rajeev Malhotra, Eric M. Isselbacher, Mark E. Lindsay

Research output: Contribution to journalArticle

12 Citations (Scopus)

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

Fingerprint

smooth muscle
Thoracic Aortic Aneurysm
muscle cells
Vascular Smooth Muscle
Smooth Muscle Myocytes
Smooth Muscle
Muscle
Contractile Proteins
chromatin
mutations
Cytoskeleton
Chromatin
Long Noncoding RNA
proteins
Actomyosin
pathogenesis
Mutation
phenotype
Histone Deacetylases
Chromatin Assembly and Disassembly

ASJC Scopus subject areas

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

Cite this

Lino Cardenas, C. L., Kessinger, C. W., Cheng, Y., MacDonald, C., MacGillivray, T., Ghoshhajra, B., ... 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

An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. / Lino Cardenas, Christian L.; Kessinger, Chase W.; Cheng, Yisha; MacDonald, Carolyn; MacGillivray, Thomas; Ghoshhajra, Brian; Huleihel, Luai; Nuri, Saifar; Yeri, Ashish S.; Jaffer, Farouc A.; Kaminski, Naftali; Ellinor, Patrick; Weintraub, Neal Lee; Malhotra, Rajeev; Isselbacher, Eric M.; Lindsay, Mark E.

In: Nature Communications, Vol. 9, No. 1, 1009, 01.12.2018.

Research output: Contribution to journalArticle

Lino Cardenas, CL, Kessinger, CW, Cheng, Y, MacDonald, C, MacGillivray, T, Ghoshhajra, B, Huleihel, L, Nuri, S, Yeri, AS, Jaffer, FA, Kaminski, N, Ellinor, P, Weintraub, NL, Malhotra, R, Isselbacher, EM & Lindsay, ME 2018, 'An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm', Nature Communications, vol. 9, no. 1, 1009. https://doi.org/10.1038/s41467-018-03394-7
Lino Cardenas CL, Kessinger CW, Cheng Y, MacDonald C, MacGillivray T, Ghoshhajra B et al. An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. Nature Communications. 2018 Dec 1;9(1). 1009. https://doi.org/10.1038/s41467-018-03394-7
Lino Cardenas, Christian L. ; Kessinger, Chase W. ; Cheng, Yisha ; MacDonald, Carolyn ; MacGillivray, Thomas ; Ghoshhajra, Brian ; Huleihel, Luai ; Nuri, Saifar ; Yeri, Ashish S. ; Jaffer, Farouc A. ; Kaminski, Naftali ; Ellinor, Patrick ; Weintraub, Neal Lee ; Malhotra, Rajeev ; Isselbacher, Eric M. ; Lindsay, Mark E. / An HDAC9-MALAT1-BRG1 complex mediates smooth muscle dysfunction in thoracic aortic aneurysm. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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