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THE ROLE OF ACETYL-COA METABOLISM IN EPIGENETIC REGULATION OF MYOFIBROBLAST DIFFERENTIATION
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2026-05
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Molecular & Cellular Biosciences
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http://dx.doi.org/10.34944/dspace/10209
Abstract
Heart failure (HF) features excessive extracellular matrix (ECM) deposition and cardiac remodeling mediated by myofibroblasts, a differentiated fibroblast population. Identifying mechanisms of myofibroblast formation and function could yield novel targets to impede or reverse fibrosis. Our lab has demonstrated that metabolic reprogramming involving glutaminolysis in myofibroblasts supports histone demethylation to enable myofibroblast gene expression. However, how acetyl-CoA metabolism regulates histone acetylation in myofibroblasts is unknown. ATP-citrate lyase (ACLY) synthesizes acetyl-CoA to supply de novo lipid synthesis and histone acetylation. We hypothesize that ACLY regulate histone acetylation for chromatin remodeling required for myofibroblast gene expression. We examined the role of ACLY in myofibroblast differentiation with transforming growth factor β (TGFβ)-stimulated cardiac fibroblasts (CFs) and pressure-overload induced cardiac fibrosis in transgenic mouse models. Pharmacological inhibition of ACLY reverted differentiated myofibroblasts under continuous TGFβ stimulation to a more quiescent/non-fibrotic phenotype. Investigation using a mouse model of pressure-overload revealed that loss of ACLY in post-activated, CFs prevented LV functional decline and excessive ECM deposition. Mechanistically, fibrotic stimulation increases ACLY accumulation in the nucleus where its activity is required for the myofibroblast formation. At the chromatin level, ACLY activity controls H3K27ac occupancy at promoters correlated with TGFβ-dependent gene expression and myofibroblast identity. Further, ACLY interacts with the canonical TGFβ-pathway transcription factors SMAD2/3 during TGFβ stimulation, suggesting ACLY is specifically directed to fibrotic gene loci to supply acetyl-CoA for local histone acetylation. Ongoing work is determining the mechanisms regulating ACLY chromatin interactions and whether this enzyme directly regulates chromatin remodeling complexes.
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