Suppressed Expression of T-Box Transcription Factors Is Involved in Senescence in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed; while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs.慢性阻塞性肺疾病（Chronic obstructive pulmonary disease, COPD）是全球范围内的重大公共卫生问题。COPD的病因学机制已被证实与细胞凋亡、氧化应激及炎症反应密切相关，但目前学界对于调控COPD发病机制的分子互作网络仅实现了部分阐明。为此，我们开展了一项针对COPD病因学的探索性研究，旨在鉴定参与COPD发病的关键分子因子。本研究采用了多种信息论算法，包括相关性上下文似然度（Context Likelihood of Relatedness, CLR）、精准细胞网络构建算法（Algorithm for the Reconstruction of Accurate Cellular Networks, ARACNE）以及Inferelator算法；基于人类肺上皮细胞的基因表达谱合集，我们成功挖掘出了基因间的直接功能关联。将此前研究中报道的COPD差异表达基因集与我们构建得到的转录调控网络进行叠加分析后，综合考量网络属性、已明确的COPD易感位点以及所构建网络中基因编码蛋白的结构域-结构域互作信息，我们最终预测出多个参与COPD病因学的潜在分子候选物，包括COL4A3、CFLAR、GULP1、PDCD1、CASP10、PAX3、BOK、HSPD1、PITX2及PML。此外，存在直接转录调控关系的T-box（TBX）家族基因与细胞周期蛋白依赖性激酶抑制剂2A（cyclin-dependent kinase inhibitor 2A, CDKN2A），通过调控细胞衰老途径成为COPD病因学中的核心参与因子。与肿瘤中的研究发现相悖，本研究揭示：COPD患者肺组织样本中的基因与蛋白表达呈现出细胞衰老倾向增强的特征——抗衰老介质（包括TBX转录因子、染色质修饰因子组蛋白去乙酰化酶以及沉默信息调节因子sirtuins）的表达受到抑制；而受TBX调控的细胞衰老标志物如CDKN2A、CDKN1A及CAV1，在COPD患者的外周肺组织样本中表达上调。COPD患者的肺组织中，衰老与抗衰老因子间的关键平衡向衰老方向发生了偏移。