Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy.
Dynamic DNA methylation of matrix metalloproteinase-9 in the development of diabetic retinopathy.
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DOI：
10.1038/labinvest.2016.78
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发表时间：
2016-10
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影响因子：
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糖尿病使视网膜及其毛细血管细胞中基质金属蛋白酶-9(MMP9)水平升高，激活的MMP9损伤线粒体，加速视网膜毛细血管细胞的凋亡，这是视网膜病变发生的先兆。糖尿病还有利于表观遗传修饰，调节许多基因的表达。DNA甲基化由甲基化-羟甲基化酶维持，糖尿病患者视网膜DNA甲基转移酶(DNMT)被激活。我们的目的是研究DNA甲基化在基质金属蛋白酶-9调控中的作用。定量检测高糖对视网膜内皮细胞5-甲基胞嘧啶(5mC)、5-羟甲基胞嘧啶(5hmC)的影响，以及DNMT1与羟甲基化酶(TET2)对基质金属蛋白酶-9启动子结合的影响。用TET2-siRNA验证TET2在基质金属蛋白酶-9活化中的作用。这一结果在链脲佐菌素诱导的糖尿病小鼠的视网膜中得到了证实。虽然葡萄糖增加了基质金属蛋白酶-9启动子上的Dnmt1结合，但它降低了5mC水平。在相同的启动子位置，TET2结合水平和5hmC水平均升高。TET2-siRNA可改善5hmC和MMP9转录水平的升高，保护线粒体损伤。糖尿病小鼠也表现出类似的视网膜基质金属蛋白酶-9启动子的动态DNA甲基化变化。因此，在糖尿病中，视网膜基质金属蛋白酶-9的转录在一定程度上是通过活跃的DNA甲基化-羟甲基化过程来维持的，这一机制的调节应该有助于维持线粒体的动态平衡，并抑制糖尿病视网膜病变的发生/发展。
Diabetes elevates matrix metalloproteinase-9 (MMP-9) in the retina and its capillary cells, and activated MMP-9 damages mitochondria, accelerating retinal capillary cell apoptosis, a phenomenon which precedes the development of retinopathy. Diabetes also favors epigenetic modifications regulating expression of many genes. DNA methylation is maintained by methylating-hydroxymethylating enzymes, and retinal DNA methyltransferase (Dnmt) is activated in diabetes. Our aim is to investigate the role of DNA methylation in MMP-9 regulation. Effect of high glucose on 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and binding of Dnmt1 and hydroxymethylating enzyme (Tet2) on MMP-9 promoter were quantified in retinal endothelial cells. Specific role of Tet2 in MMP-9 activation was validated using Tet2-siRNA. The results were confirmed in the retina from streptozotocin-induced diabetic mouse. Although glucose increased Dnmt1 binding at MMP-9 promoter, it decreased 5mC levels. At the same promoter site, Tet2 binding and 5hmC levels were elevated. Tet2-siRNA ameliorated increase in 5hmC and MMP-9 transcription, and protected mitochondrial damage. Diabetic mice also presented similar dynamic DNA methylation changes in the retinal MMP-9 promoter. Thus, in diabetes transcription of retinal MMP-9 is maintained, in part, by an active DNA methylation-hydroxymethylation process, and regulation of this machinery should help maintain mitochondrial homeostasis and inhibit the development/ progression of diabetic retinopathy.
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影响因子：
6.1
作者：
Kowluru RA;Zhong Q;Santos JM
通讯作者：
Santos JM
影响因子：
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作者：
Kern, Timothy S.
通讯作者：
Kern, Timothy S.
影响因子：
4.4
作者：
Medvedeva YA;Fridman MV;Oparina NJ;Malko DB;Ermakova EO;Kulakovskiy IV;Heinzel A;Makeev VJ
通讯作者：
Makeev VJ
DOI：
10.1016/s0006-291x(02)02283-0
发表时间：
2002-10-04
影响因子：
3.1
作者：
Chicoine, É;Estève, PO;St-Pierre, Y
通讯作者：
St-Pierre, Y
影响因子：
--
作者：
Kowluru RA;Santos JM;Mishra M
通讯作者：
Mishra M