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首页> 外文期刊>Molecular and Cellular Biology >Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis
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Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis

机译：特发性肺纤维化中组蛋白去乙酰化和高甲基化之间的相互作用抑制IP-10

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Targeted repression of a subset of key genes involved in tissue remodeling is a cardinal feature of idiopathic pulmonary fibrosis (IPF). The mechanism is unclear but is potentially important in disease pathogenesis and therapeutic targeting. We have previously reported that defective histone acetylation is responsible for the repression of the antifibrotic cyclooxygenase-2 gene. Here we extended our study to the repression of another antifibrotic gene, the potent angiostatic chemokine gamma interferon (IFN-γ)-inducible protein of 10 kDa (IP-10), in lung fibroblasts from patients with IPF. We revealed that this involved not only histone deacetylation, as with cyclooxygenase-2 repression, but also histone H3 hypermethylation, as a result of decreased recruitment of histone acetyltransferases and increased presence of histone deacetylase (HDAC)-containing repressor complexes, histone methyltransferases G9a and SUV39H1, and heterochromatin protein 1 at the IP-10 promoter, leading to reduced transcription factor binding. More importantly, treatment of diseased cells with HDAC or G9a inhibitors similarly reversed the repressive histone deacetylation and hypermethylation and restored IP-10 expression. These findings strongly suggest that epigenetic dysregulation involving interactions between histone deacetylation and hypermethylation is responsible for targeted repression of IP-10 and potentially other antifibrotic genes in fibrotic lung disease and that this is amenable to therapeutic targeting.
机译：靶向抑制参与组织重塑的关键基因子集是特发性肺纤维化（IPF）的主要特征。该机制尚不清楚，但在疾病发病机理和治疗靶向中可能潜在重要。我们以前曾报道过，组蛋白乙酰化缺陷是抗纤维化环氧合酶2基因抑制的原因。在这里，我们将研究扩展到在IPF患者的肺成纤维细胞中抑制另一种抗纤维化基因，即10 kDa（IP-10）的有效血管抑制趋化因子γ干扰素（IFN-γ）诱导蛋白。我们发现，这不仅涉及组蛋白脱乙酰化（如环氧合酶2抑制），还涉及组蛋白H3甲基化过度，这是由于组蛋白乙酰转移酶募集减少和含组蛋白脱乙酰酶（HDAC）阻遏物复合物，组蛋白甲基转移酶G9a和SUV39H1和IP-10启动子上的异染色质蛋白1，导致转录因子结合减少。更重要的是，用HDAC或G9a抑制剂治疗患病细胞同样可以逆转抑制性组蛋白去乙酰化和高甲基化，并恢复IP-10表达。这些发现强烈表明，涉及组蛋白脱乙酰基化和甲基化过度之间相互作用的表观遗传失调是导致IP-10和纤维化性肺病中潜在的其他抗纤维化基因被靶向抑制的原因，并且这适于治疗靶向。

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