Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

纤维化疾病仍然是发病率和死亡率的主要原因，但几乎没有有效的治疗方法。所有纤维化病症的潜在病理是肌成纤维细胞的活性。我们使用来自 Dupuytren 病 (DD) 患者新鲜切除的疾病组织的细胞，这是一种手掌的局部纤维化疾病，我们试图确定纤维化疾病的新治疗靶点。我们假设肌成纤维细胞在纤维化疾病中的持续活性可能涉及表观遗传修饰。使用经过验证的遗传学主导的全基因组关联研究 (GWAS) 数据目标优先排序算法 (Pi) 和广泛的表观遗传抑制剂筛选，ACTA2和COL1A1. 基因组分析显示，EP300 在与多种促纤维化途径相关基因相关的增强子上高度富集，化学探针 SGC-CBP30 对 CREBBP/EP300 抑制的广泛转录组学和蛋白质组学分析表明，胶原蛋白 VI (Col VI) 是显着的下游调节剂肌成纤维细胞活性。靶向 Col VI 敲低导致促纤维化功能显着降低，包括肌成纤维细胞收缩力、细胞外基质 (ECM) 产生、趋化性和伤口愈合。Col VI 作为纤维化的主要决定因素的进一步证据是它在 Dupuytren 结节和特发性肺纤维化 (IPF) 的纤维化病灶中的大量表达。因此，Col VI 可能代表一系列纤维化疾病的易处理治疗靶点。