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

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.

SWI/SNF remains localized to chromatin in the presence of SCHLAP1

“…Additionally, we identified high levels of SMARCA4 associated with MALAT1, while SFPQ was lower at this gene ( Fig 4A,B). A recent report showed a functional interaction between SMARCA4, HDAC9, and MALAT1, further supporting the specificity of our result 23 . The broad pattern of enrichment suggests SWI/SNF may have a frequent interaction with RNA that might not be sequence specific.…”

“…As SCHLAP1 did not exert broad effects on SWI/SNF occupancy, we next investigated whether SWI/SNF interacts with other lncRNA. Numerous reports suggest a role for lncRNASWI/SNF interactions [18][19][20][21][22][23] . We performed crosslinked RIPseq for SMARCA4 and a general splicing factor that would not be expected to have a similar interactions as a chromatin remodeler ( Splicing Factor Proline And Glutamine Rich SFPQ ) in 22Rv1 cells in LNCaP cells (Fig.…”

HDAC9 complex inhibition improves smooth muscle–dependent stenotic vascular disease

“…Identification of HDAC9 targets in cells exposed to the R179H mutant allele of ACTA2. We previously identified an epigenetic remodeling complex activated in VSMCs (HDAC9-BRG1-MALAT1) under the influence of genetic mutations that cause aortic aneurysm (10). However, some forms of genetically triggered aortic disease (GTAD) such as those caused by mutations in the ACTA2 or MYH11 gene also cause stenotic disease (6,8).…”

“…Recently, we described one such pathway active in TAA pathogenesis consisting of the histone deacetylase, HDAC9, the chromatin remodeling protein Brahma-related gene 1 (BRG1), and the long noncoding RNA (lncRNA), MALAT1 (10). This HDAC9 chromatin-modifying complex is recruited to the promoters Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection.…”

“…Among other functions, the HDAC9 complex recruits Polycomb repressive complex 2 (PRC2) to catalyze the trimethylation of histone 3 on lysine 27 (H3K27) through EZH2, its enzymatic subunit. Inhibition of the HDAC9 complex slowed aneurysm progression in conjunction with decreased H3K27 trimethylation and the restoration of contractile protein expression (10,11). Genetic evidence in humans implicates the HDAC9 locus in the pathogenesis of not only aneurysms, but also ischemic arterial disease such as coronary artery disease and large vessel ischemic stroke (12,13).…”