Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci
Phosphatidylinositol 3-Kinase (PI3K) Signaling via Glycogen Synthase Kinase-3 (Gsk-3) Regulates DNA Methylation of Imprinted Loci
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DOI：
10.1074/jbc.m110.170704
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发表时间：
2010-12-31
影响因子：
4.8
通讯作者：
Phiel, Christopher J.
中科院分区：
文献类型：
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作者：
Popkie, Anthony P.;Zeidner, Leigh C.;Phiel, Christopher J.
糖原合成酶激酶-3（Gsk-3）同种型，Gsk-3 α和Gsk-3 β，是组成型活性的，在很大程度上是参与信号转导的抑制性激酶。强调其生物学意义，改变GSK-3活性已牵连到糖尿病，阿尔茨海默病，精神分裂症和双相情感障碍。在这里，我们证明了在小鼠胚胎干细胞中Gsk-3 α和Gsk-3 β的缺失导致从头DNA甲基转移酶Dnmt 3a 2的表达减少，导致印迹基因Igf 2，H19和Igf 2 r的错误表达和其相应的印迹控制区域的低甲基化。用GSK-3抑制剂锂处理野生型胚胎干细胞和神经干细胞，表型复制了这些印记位点的DNA低甲基化。我们发现，磷脂酰肌醇3-激酶（PI 3 K）介导的Akt激活对GSK-3的抑制也会导致这些印迹位点的DNA甲基化降低。最后，我们发现，N-Myc是一个有效的GSK-3依赖的调节Dnmt 3a 2的表达。总之，我们已经确定了一个信号转导途径，是能够改变DNA甲基化的印记基因座。
Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3 alpha and Gsk-3 beta, are constitutively active, largely inhibitory kinases involved in signal transduction. Underscoring their biological significance, altered Gsk-3 activity has been implicated in diabetes, Alzheimer disease, schizophrenia, and bipolar disorder. Here, we demonstrate that deletion of both Gsk-3 alpha and Gsk-3 beta in mouse embryonic stem cells results in reduced expression of the de novo DNA methyltransferase Dnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and Igf2r and hypomethylation of their corresponding imprinted control regions. Treatment of wild-type embryonic stem cells and neural stem cells with the Gsk-3 inhibitor, lithium, phenocopies the DNA hypomethylation at these imprinted loci. We show that inhibition of Gsk-3 by phosphatidylinositol 3-kinase (PI3K)-mediated activation of Akt also results in reduced DNA methylation at these imprinted loci. Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary, we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci.