Chromatin-Mediated Reversion of Fibroblast Fate in Heart Failure.

Pathological cardiac fibrosis is a central driver of heart failure progression, arising from persistent myofibroblast activation and excessive extracellular matrix deposition following injury and chronic stress. While transient fibroblast activation is required for tissue repair, failure to resolve this state leads to maladaptive remodeling, loss of compliance, and contractile dysfunction. TGF-β/SMAD signaling is a dominant regulator of fibroblast activation, and its persistence promotes progressive heart failure. Despite this central role, therapeutic strategies directly targeting TGF-β have failed clinically, and the chromatin mechanisms that govern the magnitude, duration, and reversibility of profibrotic gene programs remain poorly defined. Our preliminary data identify B-cell–specific Moloney murine leukemia virus integration site 1 (Bmi1), a core component of Polycomb repressive complex 1 (PRC1), as a previously unrecognized epigenetic gatekeeper that restrains SMAD3-driven fibrosis in cardiac fibroblasts. Using fibroblast-specific Bmi1 knockout models, we demonstrate that loss of Bmi1 exacerbates pressure-overload–induced fibrosis and cardiac dysfunction. This is accompanied by reduced RING1A/B-dependent H2AK119 monoubiquitination (H2AK119ub), increased chromatin accessibility at the SMAD3 locus, elevated SMAD3 expression, and enhanced myofibroblast differentiation. Chromatin accessibility assays (ATAC-seq) directly link loss of Bmi1-mediated repression to increased accessibility at the SMAD3 locus, indicating that disruption of this epigenetic checkpoint converts adaptive repair signaling into a chronic fibrotic program. We hypothesize that Bmi1-dependent H2AK119ub epigenetically restrains SMAD3 transcription to enable myofibroblast reversion to a quiescent state and promote fibrosis resolution. Leveraging our extensive expertise in epigenetic regulation of fibroblast fate, this project will define how Bmi1-PRC1-mediated chromatin remodeling governs fibroblast plasticity and assess its therapeutic potential for heart failure.