Histone Acetyltransferases p300 and CBP Coordinate Distinct Chromatin Remodeling Programs in Vascular Smooth Muscle...

Area of Science:

• Cardiovascular Biology
• Epigenetics
• Cellular Regulation

Background:

• Vascular smooth muscle cell (VSMC) phenotypic switching is implicated in cardiovascular diseases.
• Epigenetic regulators, such as TET2, are key in controlling VSMC phenotype.
• The roles of homologous histone acetyl-transferases p300 and CREB-binding protein (CBP) in VSMC regulation were previously unknown.

Purpose of the Study:

• To investigate the distinct roles of p300 and CBP in VSMC phenotypic switching.
• To elucidate the molecular mechanisms underlying p300 and CBP function in VSMC regulation.
• To assess the therapeutic potential of targeting p300 or CBP in cardiovascular disease models.

Main Methods:

• Assessed p300 and CBP roles using knockdown in human VSMCs.
• Utilized inducible smooth muscle-specific knockout mice (iKO) for p300 and CBP.
• Analyzed human intimal hyperplasia and cardiac allograft vasculopathy samples.

Main Results:

• p300 and CBP exhibited opposing functions: p300 promoted contractile proteins and inhibited migration, while CBP enhanced migration and inhibited contractile genes.
• p300^iKO mice showed severe intimal hyperplasia, whereas CBP^iKO mice were protected.
• p300 interacts with TET2 to regulate histone acetylation and DNA hydroxymethylation, while CBP recruits histone deacetylases (HDACs) and inhibits TET2 expression.

Conclusions:

• p300 and CBP have nonredundant, opposing functions in VSMC phenotype regulation.
• These histone acetyl-transferases coordinate chromatin modifications via distinct interactions with TET2 and HDACs.
• Targeting specific histone acetyl-transferases presents a potential therapeutic strategy for cardiovascular diseases.