Valenzi Eleanor, Jia Minxue, Gerges Peter, Fan Jingyu, Tabib Tracy, Behara Rithika, Zhou Yuechen, Sembrat John, Das Jishnu, Benos Panayiotis V, Singh Harinder, Lafyatis Robert
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Pittsburgh.
Division of Rheumatology and Clinical Immunology, University of Pittsburgh.
bioRxiv. 2024 Oct 28:2024.10.23.619858. doi: 10.1101/2024.10.23.619858.
Pulmonary fibrosis, including systemic sclerosis-associated interstitial lung disease (SSc-ILD), involves myofibroblasts and SPP1 macrophages as drivers of fibrosis. Single-cell RNA sequencing has delineated fibroblast and macrophages transcriptomes, but limited insight into transcriptional control of profibrotic gene programs. To address this challenge, we analyzed multiomic snATAC/snRNA-seq on explanted SSc-ILD and donor control lungs. The neural network tool ChromBPNet inferred increased TF binding at single base pair resolution to profibrotic genes, including CTHRC1 and ADAM12, in fibroblasts and SPP1 and CCL18 in macrophages. The novel algorithm HALO confirmed AP-1, RUNX, and EGR TF activity controlling profibrotic gene programs and established TF-regulatory element-gene networks. This TF action atlas provides comprehensive insights into the transcriptional regulation of fibroblasts and macrophages in healthy and fibrotic human lungs.
肺纤维化，包括系统性硬化症相关间质性肺病（SSc-ILD），涉及肌成纤维细胞和SPP1巨噬细胞作为纤维化的驱动因素。单细胞RNA测序已经描绘了成纤维细胞和巨噬细胞的转录组，但对促纤维化基因程序的转录控制了解有限。为了应对这一挑战，我们分析了移植的SSc-ILD和供体对照肺的多组学snATAC/snRNA-seq。神经网络工具ChromBPNet在单碱基对分辨率下推断出在成纤维细胞中促纤维化基因（包括CTHRC1和ADAM12）以及巨噬细胞中SPP1和CCL18的转录因子结合增加。新算法HALO证实了AP-1、RUNX和EGR转录因子活性控制促纤维化基因程序，并建立了转录因子-调控元件-基因网络。这个转录因子作用图谱为健康和纤维化人类肺中成纤维细胞和巨噬细胞的转录调控提供了全面的见解。
