A Transcriptional Switch Governs Fibroblast Activation in Heart Disease
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ABSTRACT:
PROVIDER: PRJNA655922 | ENA |
REPOSITORIES: ENA
Dataset's files
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|---|---|---|---|---|
| SRR12413800_1.fastq.gz | Fastqsanger.gz | |||
| SRR12413800_2.fastq.gz | Fastqsanger.gz | |||
| SRR12413801_1.fastq.gz | Fastqsanger.gz | |||
| SRR12413801_2.fastq.gz | Fastqsanger.gz | |||
| SRR12413802_1.fastq.gz | Fastqsanger.gz |
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Project description:In diseased organs, stress-activated signaling cascades alter chromatin, triggering maladaptive cell state transitions. Fibroblast activation is a common tissue stress response that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains obscure. Pharmacologic BET inhibition alleviates cardiac dysfunction, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here, we leverage single-cell epigenomic interrogation of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch underlying fibroblast activation. 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 novel DNA elements whose accessibility dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer regulating 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. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction, and also demonstrate its upregulation upon activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide new trans- and cis- targets for treating fibrotic disease.
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Project description: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 unclear1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use 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. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.
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Project description:RNA-binding proteins control gene expression in cardiac fibroblasts during TGFb-driven fibrotic responses, including the eukaryotic translation initiation factor 4G2 (eIF4G2), which was known to facilitate alternative mRNA translation during cellular stresses. However, the precise role of eIF4G2 in cardiac fibroblast activation in response to fibrotic stress remains unclear. In this study, we found increased eIF4G2 protein levels in the hearts of heart failure patients and myocardial infarcted mice, as well as in TGFb-treated immortalized human and primary mouse cardiac fibroblasts. Depletion of eIF4G2 led to predominant translational downregulation of genes that are enriched in focal adhesion and extracellular matrix pathways. eIF4G2 knockdown reduced the proliferation, migration, and collagen secretion of TGFb-treated cardiac fibroblasts. Mechanistically, we found that the translation of IGFBP7 mRNA relies on eIF4G2, which is crucial for ECM production in response to pro-fibrotic stimuli. The interaction between eIF4G2 and a DEAD box RNA helicase DDX24 can regulate IGFBP7 protein expression in cardiac fibroblasts. Together, these findings suggest that the TGFb-eIF4G2-IGFBP7 axis establishes a novel translational regulatory circuit that governs cardiac fibroblast activation. Furthermore, conditional knockout of Eif4g2 in POSTN-positive myofibroblasts reduced cardiac fibrosis in the myocardial infarction mouse model, thus improving cardiac function. Our study provides insights into the molecular mechanism of eIF4G2-mediated translational regulation of crucial physiological mRNAs during cardiac fibroblast activation.
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