A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease

Abstract

In diseased organs, stress-activated signaling cascades alter chromatin, triggering broad shifts in transcription and cell state that exacerbate pathology. Fibroblast activation is a common stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains poorly understood1,2. Pharmacologic inhibition of the BET family of transcriptional coactivators alleviates cardiac dysfunction and associated fibrosis, providing a tool to mechanistically interrogate maladaptive fibroblast states and modulate their plasticity as a potential therapeutic approach3–8. Here, we leverage dynamic single cell transcriptomic and epigenomic interrogation of heart tissue with and without BET inhibition to reveal a reversible transcriptional switch underlying stress-induced fibroblast activation. Transcriptomes of resident cardiac fibroblasts demonstrated robust and rapid toggling between the quiescent fibroblast and activated myofibroblast state in a manner that directly correlated with BET inhibitor exposure and cardiac function. Correlation of single cell chromatin accessibility with cardiac function revealed a novel set of reversibly accessible DNA elements that correlated with disease severity. Among the most dynamic elements was an enhancer regulating the transcription factor MEOX1, which was specifically expressed in activated myofibroblasts, occupied putative regulatory elements of a broad fibrotic gene program, and was required for TGFβ-induced myofibroblast activation. CRISPR interference of the most dynamic cis-element within the enhancer, marked by nascent transcription, prevented TGFβ-induced activation of Meox1. These findings identify MEOX1 as a central regulator of stress-induced myofibroblast activation associated with cardiac dysfunction. The plasticity and specificity of the BET-dependent regulation of MEOX1 in endogenous tissue fibroblasts provides new trans- and cis- targets for treating fibrotic disease.

Bromodomain and Extraterminal Inhibition Blocks Inflammation-Induced Cardiac Dysfunction and SARS-CoV-2 Infection (Pre-Clinical)

“…3b ). Consistently, recently identified markers of fibroblast activation 25 also increased, including MEOX1, SERPINE1 (also known as plasminogen activator inhibitor-1 which induces clotting), TNC, VEGFC , and IL4R , ( Fig. 3c,d ).…”

CellWalker integrates single-cell and bulk data to resolve regulatory elements across cell types in complex tissues

“…Here, we applied CellWalker to neurodevelopment. In another study, we used CellWalker to map transcriptional disease states from mouse heart data to scATAC-seq data in matched tissues and uncovered cell type-specific enhancers activated by stress [31] Fig. S3).…”

Lineage-specific regulatory changes in the pathological cardiac remodeling of hypertrophy cardiomyopathy unraveled by single-nucleus RNA-seq and spatial transcriptomics

“…10 A recent study demonstrated that MEOX1 regulated the pro-fibrotic function and was implicated in the fibrosis of multiple human organs including the heart, liver, lung and kidney. 41 AEBP1 (also named ACLP ) has been implicated in the fibroblast activation of lung fibrosis. 42 However, our study also identified an array of novel genes and pathways that have not been explicitly implicated in fibrosis.…”