A Transcriptional Switch Governs Fibroblast Activation in Heart Disease

Abstract

In diseased organs, stress‐activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear. Pharmacological inhibition of bromodomain and extra‐terminal domain (BET) proteins alleviates cardiac dysfunction, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. We used single‐cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single‐cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ‐induced fibroblast activation. We identified MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction. Our ongoing work focus on further elucidating the molecular mechanism of fibroblast activation and exploring cellular cross‐talk between fibroblast and other cardiac cell populations in heart disease.