Hong Jason, Wong Brenda, Rhodes Christopher J, Kurt Zeyneb, Schwantes-An Tae-Hwi, Mickler Elizabeth A, Gräf Stefan, Eyries Mélanie, Lutz Katie A, Pauciulo Michael W, Trembath Richard C, Montani David, Morrell Nicholas W, Wilkins Martin R, Nichols William C, Trégouët David-Alexandre, Aldred Micheala A, Desai Ankit A, Tuder Rubin M, Geraci Mark W, Eghbali Mansoureh, Stearman Robert S, Yang Xia
bioRxiv. 2023 Jan 16:2023.01.12.523812. doi: 10.1101/2023.01.12.523812.
Pulmonary arterial hypertension (PAH) remains an incurable and often fatal disease despite currently available therapies. Multiomics systems biology analysis can shed new light on PAH pathobiology and inform translational research efforts. Using RNA sequencing on the largest PAH lung biobank to date (96 disease and 52 control), we aim to identify gene co-expression network modules associated with PAH and potential therapeutic targets. Co-expression network analysis was performed to identify modules of co-expressed genes which were then assessed for and prioritized by importance in PAH, regulatory role, and therapeutic potential via integration with clinicopathologic data, human genome-wide association studies (GWAS) of PAH, lung Bayesian regulatory networks, single-cell RNA-sequencing data, and pharmacotranscriptomic profiles. We identified a co-expression module of 266 genes, called the pink module, which may be a response to the underlying disease process to counteract disease progression in PAH. This module was associated not only with PAH severity such as increased PVR and intimal thickness, but also with compensated PAH such as lower number of hospitalizations, WHO functional class and NT-proBNP. GWAS integration demonstrated the pink module is enriched for PAH-associated genetic variation in multiple cohorts. Regulatory network analysis revealed that BMPR2 regulates the main target of FDA-approved riociguat, GUCY1A2, in the pink module. Analysis of pathway enrichment and pink hub genes (i.e. ANTXR1 and SFRP4) suggests the pink module inhibits Wnt signaling and epithelial-mesenchymal transition. Cell type deconvolution showed the pink module correlates with higher vascular cell fractions (i.e. myofibroblasts). A pharmacotranscriptomic screen discovered ubiquitin-specific peptidases (USPs) as potential therapeutic targets to mimic the pink module signature. Our multiomics integrative study uncovered a novel gene subnetwork associated with clinicopathologic severity, genetic risk, specific vascular cell types, and new therapeutic targets in PAH. Future studies are warranted to investigate the role and therapeutic potential of the pink module and targeting USPs in PAH.
尽管目前已有多种治疗方法，但肺动脉高压（PAH）仍然是一种无法治愈且往往致命的疾病。多组学系统生物学分析能够为PAH的病理生物学研究提供新的思路，并为转化医学研究提供信息。我们利用RNA测序技术，对迄今为止最大的PAH肺组织生物样本库（96例疾病样本和52例对照样本）进行分析，旨在识别与PAH相关的基因共表达网络模块以及潜在的治疗靶点。通过共表达网络分析，我们识别出了共表达基因模块，然后通过与临床病理数据、PAH的全基因组关联研究（GWAS）、肺贝叶斯调控网络、单细胞RNA测序数据以及药物转录组学图谱进行整合，评估这些模块在PAH中的重要性、调控作用和治疗潜力，并进行优先级排序。我们识别出了一个由266个基因组成的共表达模块，称为粉色模块，它可能是对潜在疾病过程的一种反应，以对抗PAH中的疾病进展。该模块不仅与PAH的严重程度相关，如肺血管阻力（PVR）增加和内膜厚度增加，还与代偿性PAH相关，如住院次数减少、世界卫生组织功能分级和N末端脑钠肽前体（NT-proBNP）降低。GWAS整合分析表明，粉色模块在多个队列中富含与PAH相关的遗传变异。调控网络分析显示，在粉色模块中，骨形态发生蛋白受体2（BMPR2）调控着美国食品药品监督管理局（FDA）批准的利奥西呱的主要靶点鸟苷酸环化酶1A2（GUCY1A2）。通路富集分析和粉色枢纽基因（即炭疽毒素受体1（ANTXR1）和分泌型卷曲相关蛋白4（SFRP4））分析表明，粉色模块抑制Wnt信号通路和上皮-间质转化。细胞类型反卷积分析显示，粉色模块与较高的血管细胞分数（即肌成纤维细胞）相关。药物转录组学筛选发现泛素特异性肽酶（USP）作为潜在的治疗靶点，可模拟粉色模块特征。我们的多组学综合研究揭示了一个与PAH临床病理严重程度、遗传风险、特定血管细胞类型和新治疗靶点相关的新型基因子网。未来有必要开展进一步研究，以探究粉色模块在PAH中的作用和治疗潜力，以及靶向USP治疗PAH的效果。
