Idiopathic pulmonary fibrosis (IPF), a devastating, fibroproliferative, chronic lung disorder, is associated with expansion of fibroblasts/myofibroblasts, which leads to excessive production and deposition of extracellular matrix. IPF is typically clinically identified as end-stage lung disease, after fibrotic processes are well-established and advanced. Fibroblasts have been shown to be critically important in the development and progression of IPF. We hypothesize that differential chromatin access can drive genetic differences in IPF fibroblasts relative to healthy fibroblasts. To this end, we performed assay of transposase-accessible chromatin sequencing to identify differentially accessible regions within the genomes of fibroblasts from healthy and IPF lungs. Multiple motifs were identified to be enriched in IPF fibroblasts compared with healthy fibroblasts, including binding motifs for TWIST1 and FOXA1. RNA sequencing identified 93 genes that could be annotated to differentially accessible regions. Pathway analysis of the annotated genes identified cellular adhesion, cytoskeletal anchoring, and cell differentiation as important biological processes. In addition, single nucleotide polymorphism analysis showed that linkage disequilibrium blocks of IPF risk single nucleotide polymorphisms with IPF-accessible regions that have been identified to be located in genes that are important in IPF, including MUC5B, TERT, and TOLLIP. Validation studies in isolated lung tissue confirmed increased expression for TWIST1 and FOXA1 in addition to revealing SHANK2 and CSPR2 as novel targets. Thus, modulation of differential chromatin access may be an important mechanism in the pathogenesis of lung fibrosis.

特发性肺纤维化 (IPF) 是一种破坏性的、纤维增殖性的慢性肺部疾病，与成纤维细胞/肌成纤维细胞的扩张有关，这会导致细胞外基质的过度产生和沉积。IPF 通常在临床上被确定为终末期肺病，在纤维化过程得到完善和发展之后。成纤维细胞已被证明在 IPF 的发展和进展中至关重要。我们假设不同的染色质访问可以驱动 IPF 成纤维细胞相对于健康成纤维细胞的遗传差异。为此，我们对转座酶可及的染色质测序进行了测定，以识别健康和 IPF 肺成纤维细胞基因组内的差异可及区域。与健康的成纤维细胞相比，IPF 成纤维细胞中富含多种基序，包括 TWIST1 和 FOXA1 的结合基序。RNA 测序确定了 93 个基因，这些基因可以被注释到差异可及的区域。注释基因的通路分析将细胞粘附、细胞骨架锚定和细胞分化确定为重要的生物学过程。此外，单核苷酸多态性分析表明，IPF 的连锁不平衡块可能与 IPF 可接近区域发生单核苷酸多态性，这些区域已被确定位于 IPF 中重要的基因中，包括 MUC5B、TERT 和 TOLLIP。除了揭示 SHANK2 和 CSPR2 作为新靶点外，在离体肺组织中的验证研究证实了 TWIST1 和 FOXA1 的表达增加。因此，