Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA methylation of imprinted loci.
Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3α and Gsk-3β, 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-3α and Gsk-3β 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.
Graduate Program in Molecular, Cellular and Developmental Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Anthony P
AP
Popkie
Leigh C
LC
Zeidner
Ashley M
AM
Albrecht
Anthony
A
D'Ippolito
Sigrid
S
Eckardt
David E
DE
Newsom
Joanna
J
Groden
Bradley W
BW
Doble
Bruce
B
Aronow
K John
KJ
McLaughlin
Peter
P
White
Christopher J
CJ
Phiel
D000818:Animals; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018392:Genomic Imprinting; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D015398:Signal Transduction
C094335:H19 long non-coding RNA; C513121:IGF2 protein, mouse; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; D017527:Receptor, IGF Type 2; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D038362:Glycogen Synthase Kinase 3