Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis
Repression of IP-10 by Interactions between Histone Deacetylation and Hypermethylation in Idiopathic Pulmonary Fibrosis
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DOI：
10.1128/mcb.01527-09
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发表时间：
2010-06-15
影响因子：
5.3
通讯作者：
Pang, Linhua
中科院分区：
文献类型：
--
作者：
Coward, William R.;Watts, Keira;Pang, Linhua
对参与组织重塑的关键基因子集的靶向抑制是特发性肺纤维化（IPF）的一个主要特征。其机制尚不清楚，但在疾病发病机制和治疗靶向方面具有潜在的重要性。我们以前曾报道，有缺陷的组蛋白乙酰化是负责抑制抗纤维化环氧合酶-2基因。在这里，我们将我们的研究扩展到另一个抗纤维化基因，强效血管生成抑制趋化因子γ干扰素（IFN-γ）诱导蛋白10 kDa（IP-10），在IPF患者的肺成纤维细胞的抑制。我们发现，这不仅涉及组蛋白去乙酰化，与环氧合酶-2抑制，而且组蛋白H3超甲基化，由于减少招募组蛋白乙酰转移酶和增加存在的组蛋白去乙酰化酶（HDAC）-含有阻遏复合物，组蛋白甲基转移酶G9 a和SUV 39 H1，异染色质蛋白1在IP-10启动子，导致转录因子结合减少。更重要的是，用HDAC或G9 a抑制剂治疗病变细胞类似地逆转了抑制性组蛋白脱乙酰化和超甲基化，并恢复了IP-10表达。这些发现强烈表明，涉及组蛋白去乙酰化和高甲基化之间相互作用的表观遗传失调是导致纤维化肺病中IP-10和潜在的其他抗纤维化基因的靶向抑制的原因，并且这适合于治疗靶向。
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-gamma)-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.