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The derepression of transposable elements in lung cells is associated with the inflammatory response and gene activation in idiopathic pulmonary fibrosis
Mobile DNA ( IF 4.9 ) Pub Date : 2021-06-09 , DOI: 10.1186/s13100-021-00241-3
Mahboubeh R Rostami 1 , Martina Bradic 1, 2
Affiliation  

Transposable elements (TEs) are repetitive sequences of viral origin that compose almost half of the human genome. These elements are tightly controlled within cells, and if activated, they can cause changes in both gene regulation and immune viral responses that have been associated with several chronic inflammatory diseases in humans. As oxidants are potent activators of TEs, and because oxidative injury is a major risk factor in relation to idiopathic pulmonary fibrosis (IPF), we hypothesized that TEs might be involved in the regulation of gene expression and so contribute to inflammation in cases of IPF. IPF is a fatal lung disease that involves the gradual replacement of the alveolar tissue with fibrotic scars as well as the accumulation of inflammatory cells in the lower respiratory tract. Although IPF is known to occur as a result of the complex interaction between age, environmental risk factors (i.e., oxidative stress) and genetics, the relative contributions of these factors to the disease remain unclear. To determine whether TEs are associated with IPF, we compared the transcriptional profiles of the genes and TEs of lung cells obtained from both healthy donors and IPF patients. We quantified TE and gene expression levels using a published bulk RNA-seq dataset containing 24 subjects (16 donors and eight IPF patients), including three lung-cell types per subject, as well as an scRNA-seq dataset concerning 16 subjects (eight donors and eight IPF patients). We found evidence of TE dysregulation in the alveolar type II lung cells and alveolar macrophages of the IPF patients. In addition, the activation of the LINE1 family of elements in IPF is associated with the increased expression of TE cellular regulators (MOV10, IFI16, SAMHD1, and APOBECG3), interferon-stimulating genes (ISG15, IFI6, IFI27, IFI44, and OAS1), chemokines (CX3CL1 and CXCL9), and interleukins (IL15RA). We also propose that TE derepression might be involved in the regulation of previously reported IPF candidate genes (MUC5B, CHL1, SPP1, and MMP7). Based on our findings, we propose that TE derepression plays an important role in the regulation of gene expression and can also prompt both the recruitment of inflammatory processes and the disruption of the immunological balance, which can lead to chronic inflammation in IPF.

中文翻译:

肺细胞中转座因子的去抑制与特发性肺纤维化中的炎症反应和基因激活有关

转座因子 (TE) 是病毒来源的重复序列,几乎构成人类基因组的一半。这些元素在细胞内受到严格控制,如果被激活,它们会导致基因调控和免疫病毒反应发生变化,这些反应与人类的几种慢性炎症性疾病有关。由于氧化剂是 TE 的有效激活剂,并且由于氧化损伤是与特发性肺纤维化 (IPF) 相关的主要危险因素,我们假设 TE 可能参与基因表达的调节,因此在 IPF 的情况下会导致炎症。IPF 是一种致命的肺部疾病,涉及逐渐用纤维化疤痕替代肺泡组织以及下呼吸道炎症细胞的积累。虽然已知 IPF 是由于年龄、环境风险因素(即氧化应激)和遗传之间的复杂相互作用而发生的,但这些因素对疾病的相对贡献仍不清楚。为了确定 TE 是否与 IPF 相关,我们比较了从健康供体和 IPF 患者获得的肺细胞基因和 TE 的转录谱。我们使用已发表的包含 24 名受试者(16 名供体和 8 名 IPF 患者)的批量 RNA-seq 数据集(包括每个受试者的三种肺细胞类型)以及涉及 16 名受试者(8 名供体)的 scRNA-seq 数据集来量化 TE 和基因表达水平和八名 IPF 患者)。我们在 IPF 患者的肺泡 II 型肺细胞和肺泡巨噬细胞中发现了 TE 失调的证据。此外,IPF 中 LINE1 家族元素的激活与 TE 细胞调节因子(MOV10、IFI16、SAMHD1 和 APOBECG3)、干扰素刺激基因(ISG15、IFI6、IFI27、IFI44 和 OAS1)、趋化因子( CX3CL1 和 CXCL9) 和白细胞介素 (IL15RA)。我们还提出 TE 去抑制可能参与先前报道的 IPF 候选基因(MUC5B、CHL1、SPP1 和 MMP7)的调节。根据我们的研究结果,我们提出 TE 去抑制在基因表达的调节中起着重要作用,并且还可以促进炎症过程的募集和免疫平衡的破坏,这可能导致 IPF 中的慢性炎症。干扰素刺激基因(ISG15、IFI6、IFI27、IFI44 和 OAS1)、趋化因子(CX3CL1 和 CXCL9)和白细胞介素(IL15RA)。我们还提出 TE 去抑制可能参与先前报道的 IPF 候选基因(MUC5B、CHL1、SPP1 和 MMP7)的调节。根据我们的研究结果,我们提出 TE 去抑制在基因表达的调节中起着重要作用,并且还可以促进炎症过程的募集和免疫平衡的破坏,这可能导致 IPF 中的慢性炎症。干扰素刺激基因(ISG15、IFI6、IFI27、IFI44 和 OAS1)、趋化因子(CX3CL1 和 CXCL9)和白细胞介素(IL15RA)。我们还提出 TE 去抑制可能参与先前报道的 IPF 候选基因(MUC5B、CHL1、SPP1 和 MMP7)的调节。根据我们的研究结果,我们提出 TE 去抑制在基因表达的调节中起着重要作用,并且还可以促进炎症过程的募集和免疫平衡的破坏,这可能导致 IPF 中的慢性炎症。
更新日期:2021-06-10
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