Annals of the rheumatic diseases · 2025
Altered AP-1, RUNX, and EGR chromatin dynamics drive human fibrotic lung disease.
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Valenzi Eleanor, Jia Minxue, Gerges Peter, Fan Jingyu, Tabib Tracy, Behera Rithika, Mao Haiyi, Xue Dan, Ju Eun Mi, Zhou Yuechen, Sembrat John C, Das Jishnu, Benos Panayiotis V, Singh Harinder, Lafyatis Robert
Аннотация
OBJECTIVES: Pulmonary fibrosis can result from autoimmune, inflammatory, or idiopathic conditions, including systemic sclerosis-associated interstitial lung disease (SSc-ILD). Previous studies have implicated myofibroblasts and SPP1hi macrophages as drivers of fibrosis in lungs, as well as other tissues. Single-cell RNA-sequencing has delineated fibroblast and macrophage transcriptomes but provides limited insight into the transcriptional control of profibrotic gene programmes.
METHODS: To determine the chromatin accessibility dynamics and transcription factors driving profibrotic gene programmes in human pulmonary fibrosis, we performed multiomic single-nucleus assay for transposase-accessible (ATAC)/RNA-sequencing on explanted SSc-ILD and control lungs. Using the neural network tool ChromBPNet, we analysed pseudobulk fibroblast and macrophage populations to infer transcription factor binding dynamics at single base-pair resolution. Hierarchical causal modelling for single-cell multiomics data (HALO), a novel algorithm developed to derive low-dimensional representations of sparse multiomics data, revealed transcription factor-regulatory element-gene networks.
RESULTS: ChromBPNet inferred increased transcription factor binding to profibrotic genes, including CTHRC1 and ADAM12 in fibroblasts, and SPP1 and CCL18 in macrophages. SSc-ILD fibroblasts showed increased binding and enhancer activity by AP-1, RUNX, and EGR transcription factors to profibrotic genes, whereas macrophages displayed enhanced binding and activity of AP-1 and basic helix-loop-helix (bHLH)-ZIP transcription factors in genes regulating the SPP1hi phenotype. HALO confirmed AP-1, RUNX, and EGR activity controlling profibrotic gene programmes.
CONCLUSIONS: These data provide comprehensive insights into the complexity of transcriptional control of SSc-ILD gene expression programmes and define specific AP-1, RUNX, and EGR enhancers in key myofibroblast marker genes CTHRC1 and ADAM12, and a bHLH-ZIP enhancer in SPP1hi macrophages.
METHODS: To determine the chromatin accessibility dynamics and transcription factors driving profibrotic gene programmes in human pulmonary fibrosis, we performed multiomic single-nucleus assay for transposase-accessible (ATAC)/RNA-sequencing on explanted SSc-ILD and control lungs. Using the neural network tool ChromBPNet, we analysed pseudobulk fibroblast and macrophage populations to infer transcription factor binding dynamics at single base-pair resolution. Hierarchical causal modelling for single-cell multiomics data (HALO), a novel algorithm developed to derive low-dimensional representations of sparse multiomics data, revealed transcription factor-regulatory element-gene networks.
RESULTS: ChromBPNet inferred increased transcription factor binding to profibrotic genes, including CTHRC1 and ADAM12 in fibroblasts, and SPP1 and CCL18 in macrophages. SSc-ILD fibroblasts showed increased binding and enhancer activity by AP-1, RUNX, and EGR transcription factors to profibrotic genes, whereas macrophages displayed enhanced binding and activity of AP-1 and basic helix-loop-helix (bHLH)-ZIP transcription factors in genes regulating the SPP1hi phenotype. HALO confirmed AP-1, RUNX, and EGR activity controlling profibrotic gene programmes.
CONCLUSIONS: These data provide comprehensive insights into the complexity of transcriptional control of SSc-ILD gene expression programmes and define specific AP-1, RUNX, and EGR enhancers in key myofibroblast marker genes CTHRC1 and ADAM12, and a bHLH-ZIP enhancer in SPP1hi macrophages.