TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing
TET2-interacting long noncoding RNA promotes active DNA demethylation of the MMP-9 promoter in diabetic wound healing
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TET2相互作用的长非编码RNA促进糖尿病伤口愈合中MMP-9启动子的主动DNA去甲基化
DOI：
10.1038/s41419-019-2047-6
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发表时间：
2019-10-25
影响因子：
9
通讯作者：
Yan, Li
中科院分区：
文献类型：
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作者：
Zhou, Liyan;Ren, Meng;Yan, Li
基质金属蛋白酶-9（MMP-9）的过度活化损害了糖尿病皮肤的伤口愈合。MMP-9的转录被TET 2激活，TET 2是一种众所周知的DNA去甲基化蛋白，可诱导糖尿病皮肤组织中MMP-9启动子的去甲基化。然而，TET 2如何靶向MMP-9启动子中的特定位点尚不清楚。在这里，我们确定了TET 2相互作用的长非编码RNA（TETILA），在人类糖尿病皮肤组织中上调。TETILA调节TET 2亚细胞定位和酶活性，间接激活MMP-9启动子去甲基化。TETILA还招募胸腺嘧啶-DNA糖基化酶（TDG），其同时与TET 2相互作用，用于碱基切除修复介导的MMP-9启动子去甲基化。总之，我们的结果表明TETILA作为MMP-9启动子中TET 2介导的去甲基化特异性位点的基因组归巢信号，从而破坏糖尿病皮肤伤口愈合的过程。
Wound healing in diabetic skin is impaired by excessive activation of matrix metalloproteinase-9 (MMP-9). MMP-9 transcription is activated by Ten-eleven translocation 2 (TET2), a well-known DNA demethylation protein that induces MMP-9 promoter demethylation in diabetic skin tissues. However, how TET2 is targeted to specific loci in the MMP-9 promoter is unknown. Here, we identified a TET2-interacting long noncoding RNA (TETILA) that is upregulated in human diabetic skin tissues. TETILA regulates TET2 subcellular localization and enzymatic activity, indirectly activating MMP-9 promoter demethylation. TETILA also recruits thymine-DNA glycosylase (TDG), which simultaneously interacts with TET2, for base excision repair-mediated MMP-9 promoter demethylation. Together, our results suggest that the TETILA serves as a genomic homing signal for TET2-mediated demethylation specific loci in MMP-9 promoter, thereby disrupting the process of diabetic skin wound healing.