DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult.
DNA methylation: A mechanism for sustained alteration of KIR4.1 expression following central nervous system insult.
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作者：
Boni JL;Kahanovitch U;Nwaobi SE;Floyd CL;Olsen ML
Kir4.1是一种胶质细胞特异性内向整流钾通道，与星形胶质细胞维持K+稳态有关。强调Kir4.1在CNS功能中的作用，编码Kir4.1的基因KCNJ 10的基因突变导致人类癫痫发作，共济失调和发育障碍。Kir4.1蛋白和mRNA丢失是持续观察到的CNS损伤，以及与过度兴奋和神经元功能障碍相关的神经系统疾病，导致Kir4.1代表有吸引力的治疗靶点的概念。尽管如此，人们对这种下调的机制知之甚少。我们实验室以前的工作表明，在星形胶质细胞成熟过程中，Kcnj 10基因的DNA低甲基化作用调节mRNA水平，而体外高甲基化导致启动子活性降低。在目前的研究中，我们利用两种截然不同的损伤模型，已知Kir4.1蛋白和mRNA的急性和慢性丢失，以评估Kcnj 10的甲基化状态，作为转录减少和随后蛋白丢失的候选分子机制。在锂-匹罗卡品癫痫模型中，检查整个海马组织和分离的星形胶质细胞，我们一致地鉴定了CpG岛2的超甲基化，其位于跨越Kcnj 10基因的大内含子区域。使用第二损伤范例，脊髓损伤的第五颈（C5）椎骨半挫伤模型，观察到惊人的相似结果。我们以前的工作表明，当星形胶质细胞成熟过程中转录增加时，同一基因区域显著低甲基化。我们的研究结果表明，DNA甲基化可以双向调节Kcnj 10的转录，并可能代表一个有针对性的分子机制，恢复星形胶质细胞Kir4.1表达后中枢神经系统的侮辱。
Kir4.1, a glial-specific inwardly rectifying potassium channel, is implicated in astrocytic maintenance of K+ homeostasis. Underscoring the role of Kir4.1 in CNS functioning, genetic mutations in KCNJ10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans. Kir4.1 protein and mRNA loss are consistently observed CNS injury, and neurological diseases linked to hyperexcitability and neuronal dysfunction, leading to the notion that Kir4.1 represents an attractive therapeutic target. Despite this, little is understood regarding the mechanisms that underpin this downregulation. Previous work by our lab revealed that DNA hypomethylation of the Kcnj10 gene functions to regulate mRNA levels during astrocyte maturation whereas hypermethylation in vitro led to decreased promoter activity. In the current study we utilized two vastly different injury models with known acute and chronic loss of Kir4.1 protein and mRNA to evaluate the methylation status of Kcnj10 as a candidate molecular mechanism for reduced transcription and subsequent protein loss. Examining whole hippocampal tissue and isolated astrocytes, in a lithium-pilocarpine model of epilepsy, we consistently identified hypermethylation of CpG island two, which resides in the large intronic region spanning the Kcnj10 gene. Strikingly similar results were observed using a second injury paradigm, a fifth cervical (C5) vertebral hemi-contusion model of spinal cord injury. Our previous work indicates the same gene region is significantly hypomethylated when transcription increases during astrocyte maturation. Our results suggest that DNA methylation can bidirectionally modulate Kcnj10 transcription and may represent a targetable molecular mechanism for the restoring astroglial Kir4.1 expression following CNS insult.
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影响因子：
2.5
作者：
Du, Yixing;Ma, Baofeng;Zhou, Min
通讯作者：
Zhou, Min
影响因子：
5.3
作者：
Djukic, Biljana;Casper, Kristen B.;McCarthy, Ken D.
通讯作者：
McCarthy, Ken D.
影响因子：
4.8
作者：
Itakura, Eisuke;Odaira, Kousuke;Inoue, Kinji
通讯作者：
Inoue, Kinji
DOI：
10.1097/nen.0b013e318267b5af
发表时间：
2012-09
影响因子：
3.2
作者：
Heuser K;Eid T;Lauritzen F;Thoren AE;Vindedal GF;Taubøll E;Gjerstad L;Spencer DD;Ottersen OP;Nagelhus EA;de Lanerolle NC
通讯作者：
de Lanerolle NC
影响因子：
4.5
作者：
Gupta, R. K.;Prasad, S.
通讯作者：
Prasad, S.