Blood-Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy.
Blood-Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy.
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DOI：
10.1161/jaha.121.021101
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发表时间：
2021-11-02
影响因子：
5.4
通讯作者：
Takeishi Y
中科院分区：
文献类型：
--
作者：
Wada K;Misaka T;Yokokawa T;Kimishima Y;Kaneshiro T;Oikawa M;Yoshihisa A;Takeishi Y
基于血液的DNA甲基化模式与疾病类型有关。FKBP脯氨酰异构酶5（FKBP 5）是一种蛋白质伴侣，已知与炎症反应相关，但扩张型心肌病（DCM）患者白细胞FKBP 5 DNA甲基化的调控机制尚不清楚。本研究招募了DCM患者（n=31）和年龄匹配和性别匹配的对照参与者（n=43）。我们使用从外周血中分离的白细胞DNA，通过甲基化特异性定量聚合酶链反应评估了5′端CpG岛以及推定启动子区域的FKBP 5 CpG（胞嘧啶-磷酸-鸟嘌呤）甲基化。在DCM患者中，基因体和启动子区域的CpG岛的FKBP 5 CpG甲基化水平显著降低。DCM患者的白细胞FKBP 5和IL-1β（白细胞介素1β）mRNA表达水平显著高于对照组。DCM患者白细胞DNMT 1和DNMT 3A蛋白表达明显降低。体外甲基化实验表明，免疫刺激后FKBP 5启动子甲基化水平降低，提示FKBP 5 CpG甲基化水平降低与FKBP 5 mRNA表达水平升高相关。使用具有压力超负荷的小鼠模型进行的组织学分析显示，FKBP 5表达细胞基本上浸润在衰竭心脏的心肌细胞中，表明免疫细胞的FKBP 5表达在心脏重塑中的可能作用。我们的研究结果证明了白细胞FKBP 5的特异性CpG低甲基化与DCM之间的联系。FKBP 5中基于血液的表观遗传修饰可能是导致DCM发病的新分子机制。
Blood‐based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. The present study enrolled patients with DCM (n=31) and age‐matched and sex‐matched control participants (n=43). We assessed FKBP5 CpG (cytosine‐phosphate‐guanine) methylation of CpG islands at the 5′ side as well as putative promoter regions by methylation‐specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte FKBP5 and IL‐1β (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that FKBP5 promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased FKBP5 CpG methylation was functionally associated with elevation of FKBP5 mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5‐expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Our findings demonstrate a link between specific CpG hypomethylation of leukocyte FKBP5 and DCM. Blood‐based epigenetic modification in FKBP5 may be a novel molecular mechanism that contributes to the pathogenesis of DCM.