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

doi:10.1038/s41467-018-03394-7

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

Nat Commun. 2018 Mar 8;9(1):1009. doi: 10.1038/s41467-018-03394-7.

Authors

Christian L Lino Cardenas^{1

2

3}, Chase W Kessinger^{2

3}, Yisha Cheng^{1

2

3}, Carolyn MacDonald^{1

2

3}, Thomas MacGillivray^{1

4}, Brian Ghoshhajra^{1

5}, Luai Huleihel^{6

7}, Saifar Nuri^{1

2

3}, Ashish S Yeri³, Farouc A Jaffer^{2

3}, Naftali Kaminski⁷, Patrick Ellinor^{2

3

8}, Neal L Weintraub⁹, Rajeev Malhotra^{2

3}, Eric M Isselbacher^{1

2

3}, Mark E Lindsay^{10

11

12

13

14}

Affiliations

¹ Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
² Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
³ Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁴ Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁵ Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁶ McGowan Institute for Regenerative Medicine and Department of Surgery, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA, 15219, USA.
⁷ Pulmonary, Critical Care, and Sleep Medicine, Yale University, 300 Cedar Street, TAC-S441D, New Haven, CT, 06510, USA.
⁸ Cardiovascular Genetics Program, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA.
⁹ Augusta University/Medical College of Georgia, 1459 Laney Walker Boulevard, CB3330, Augusta, GA, 30912, USA.
¹⁰ Thoracic Aortic Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. Lindsay.Mark@mgh.harvard.edu.
¹¹ Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. Lindsay.Mark@mgh.harvard.edu.
¹² Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. Lindsay.Mark@mgh.harvard.edu.
¹³ Cardiovascular Genetics Program, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. Lindsay.Mark@mgh.harvard.edu.
¹⁴ Pediatric Cardiology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA. Lindsay.Mark@mgh.harvard.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Actomyosin / genetics
Actomyosin / metabolism
Animals
Aorta / pathology
Aortic Aneurysm, Thoracic / genetics*
Aortic Aneurysm, Thoracic / pathology
Cell Line
Cell Nucleus / metabolism
Chromatin / metabolism
DNA Helicases / genetics*
DNA Helicases / metabolism
DNA Methylation
Disease Models, Animal
Female
Fluorescent Antibody Technique
Histone Deacetylases / genetics*
Histone Deacetylases / metabolism
Histones / metabolism
Humans
Male
Mice
Mice, Knockout
Muscle, Smooth, Vascular / cytology
Muscle, Smooth, Vascular / pathology*
Mutation
Myocytes, Smooth Muscle
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
Phenotype
Primary Cell Culture
RNA Interference
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
RNA, Small Interfering / metabolism
Repressor Proteins / genetics*
Repressor Proteins / metabolism
Signal Transduction / genetics
Transcription Factors / genetics*
Transcription Factors / metabolism
Transforming Growth Factor beta / metabolism*

Substances

Chromatin
Histones
MALAT1 long non-coding RNA, human
Malat1 long non-coding RNA, mouse
Nuclear Proteins
RNA, Long Noncoding
RNA, Small Interfering
Repressor Proteins
Transcription Factors
Transforming Growth Factor beta
Actomyosin
HDAC9 protein, human
Hdac9 protein, mouse
Histone Deacetylases
SMARCA4 protein, human
Smarca4 protein, mouse
DNA Helicases

Abstract

Publication types

MeSH terms

Substances

Grants and funding