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

Area of Science:

• Vascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Thoracic aortic aneurysm (TAA) is linked to mutations in TGF-β signaling or vascular smooth muscle cell (VSMC) cytoskeleton.
• Despite similar phenotypes, the underlying common pathogenic mechanisms for these TAA forms remain unclear.

Purpose of the Study:

• To elucidate the shared molecular mechanisms in TAA pathogenesis.
• To identify a common epigenetic pathway linking TGF-β and VSMC cytoskeleton mutations.

Main Methods:

• Investigated the formation of a ternary complex involving HDAC9, BRG1, and MALAT1 in TAA.
• Analyzed the complex's role in chromatin binding and gene expression regulation.
• Assessed the therapeutic potential of disrupting Malat1 or Hdac9 in experimental aneurysm models.

Main Results:

• Identified a shared HDAC9-MALAT1-BRG1 complex in both TAA mutation groups.
• Demonstrated that this complex represses contractile protein gene expression via H3K27 trimethylation.
• Showed that disrupting Malat1 or Hdac9 restores gene expression, improves aortic structure, and inhibits aneurysm growth.

Conclusions:

• Highlighted a common epigenetic pathway driving VSMC dysfunction in TAA.
• Proposed the HDAC9-MALAT1-BRG1 complex as a therapeutic target for TAA.
• Suggested potential therapeutic implications for other HDAC9-associated vascular diseases.