| First Author | Popkie AP | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 53 | Pages | 41337-47 |
| PubMed ID | 21047779 | Mgi Jnum | J:173141 |
| Mgi Id | MGI:5009774 | Doi | 10.1074/jbc.M110.170704 |
| Citation | Popkie AP, et al. (2010) Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci. J Biol Chem 285(53):41337-47 |
| abstractText | Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3alpha and Gsk-3beta, 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-3alpha and Gsk-3beta 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. |
