BAHCC1 Drives Smooth Muscle Plasticity and Neointima via Epigenetic Repression
Runze Tang, Yitao Huang, Takuro Shirasu, Jing Li, Amy Webb, Kaiyuan Zheng, Chengli Shen, Yiran Guo, Gaelle Auguste, Patrick Hart, Maria Murach, Xinyu Zhou, Jianjie Ma, K. Craig Kent, Gang Greg Wang, Jie Yang, Clint L. Miller, Kathleen Ann Martin, Lian-Wang GuoBACKGROUND:
Vascular smooth muscle cell (SMC) phenotypic plasticity drives neointimal hyperplasia (IH) and contributes to atherosclerosis. Epigenetic mechanisms have been implicated in SMC plasticity, but the roles of epigenetic reader proteins are poorly understood. BAHCC1 (bromo adjacent homology domain coiled-coil 1) is a newly identified reader of the gene-repression histone mark histone-3 lysine 27 trimethylation (H3K27me3). Its role in vascular remodeling is unknown.
METHODS:
We investigated BAHCC1 in human restenotic and atherosclerotic arteries and in rat and mouse arterial injury models using BAHCC1 silencing, SMC-specific deletion, and an H3K27me3-binding-deficient knock-in mutation. Mechanistic studies in human aortic SMCs integrated transcriptomic and epigenomic profiling, protein-interaction assays, and single-guide RNA-dCas9-based epigenetic editing.
RESULTS:
BAHCC1 was upregulated in human restenotic and atherosclerotic arteries and rat arteries with IH. While BAHCC1 silenc ing reduced IH in balloon-injured rat arteries, SMC-specific BAHCC1 deletion and the H3K27me3-binding-deficient mutation (BAHCC1
Y2537A
) attenuated IH in wire-injured mouse arteries. In human SMCs, mitogen induced BAHCC1 expression through nuclear factor Y subunit-α, promoting BAHCC1-dependent dedifferentiation. Integrated transcriptomics and epigenomics identified LMO7 (LIM domain only 7), an IH suppressor, as a key BAHCC1-repressed target. BAHCC1 occupancy at
CONCLUSIONS:
BAHCC1 is a previously unrecognized epigenetic driver of vascular remodeling. By reading H3K27me3 and recruiting corepressors to repress gene expression, BAHCC1 promotes pathological SMC phenotypic transition and IH, highlighting the BAHCC1 pathway as a potential therapeutic target for IH-associated vascular disease.