Key result
BAHCC1 inhibition attenuates neointimal hyperplasia by derepressing LMO7 in vascular smooth muscle cells.
Why the study?
Epigenetic reader proteins in vascular smooth muscle cell plasticity are poorly understood, and the role of the newly identified H3K27me3 reader BAHCC1 in vascular remodeling was unknown.
Does inhibiting BAHCC1 or disrupting its H3K27me3-binding activity attenuate smooth muscle cell dedifferentiation and neointimal hyperplasia in preclinical models of arterial injury?
Does inhibiting BAHCC1 or disrupting its H3K27me3-binding activity attenuate smooth muscle cell dedifferentiation and neointimal hyperplasia in preclinical models of arterial injury?
Identifies the H3K27me3 reader BAHCC1 as a novel epigenetic driver of vascular smooth muscle cell plasticity and neointimal hyperplasia via repression of LMO7, revealing a potential therapeutic target for restenosis and atherosclerosis.
BACKGROUND: 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 LMO7 required BAHCC1-H3K27me3 interaction, and LMO7 -targeted H3K27me3 enrichment through epigenetic editing repressed its expression in a BAHCC1-dependent manner. Furthermore, BAHCC1 associated with SAP30 and RBBP4/7 to form a corepressor complex. Functionally, LMO7 silencing reversed the effects of BAHCC1 knockdown on human SMC phenotype and exacerbated IH in BAHCC1 Y2537A mice. Human genetic analyses further identified BAHCC1 variants associated with cardiovascular phenotypes and BAHCC1 expression. 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.
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Tang et al. (2026) studied Neointimal hyperplasia and atherosclerosis. BAHCC1 silencing, SMC-specific BAHCC1 deletion, and H3K27me3-binding-deficient mutation (BAHCC1 Y2537A) vs. Control / wild-type models was evaluated on Neointimal hyperplasia and vascular smooth muscle cell phenotypic transition. BAHCC1 silencing, smooth muscle cell-specific deletion, and the H3K27me3-binding-deficient BAHCC1 Y2537A mutation attenuated neointimal hyperplasia via epigenetic derepression of LMO7.
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