Dnmt3a regulates both proliferation and differentiation of mouse neural stem cells.
DNA methylation is known to regulate cell differentiation and neuronal function in vivo. Here we examined whether deficiency of a de novo DNA methyltransferase, Dnmt3a, affects in vitro differentiation of mouse embryonic stem cells (mESCs) to neuronal and glial cell lineages. Early-passage neural stem cells (NSCs) derived from Dnmt3a-deficient ESCs exhibited a moderate phenotype in precocious glial differentiation compared with wild-type counterparts. However, successive passaging to passage 6 (P6), when wild-type NSCs become gliogenic, revealed a robust phenotype of precocious astrocyte and oligodendrocyte differentiation in Dnmt3a(-/-) NSCs, consistent with our previous findings in the more severely hypomethylated Dnmt1(-/-) NSCs. Mass spectrometric analysis revealed that total levels of methylcytosine in Dnmt3a(-/-) NSCs at P6 were globally hypomethylated. Moreover, the Dnmt3a(-/-) NSC proliferation rate was significantly increased compared with control from P6 onward. Thus, our work revealed a novel role for Dnmt3a in regulating both the timing of neural cell differentiation and the cell proliferation in the paradigm of mESC-derived-NSCs.
Department of Spinal Surgery, Translational Stem Cell Center, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Zhourui
Z
Wu
Kevin
K
Huang
Juehua
J
Yu
Thuc
T
Le
Masakasu
M
Namihira
Yupeng
Y
Liu
Jun
J
Zhang
Zhigang
Z
Xue
Liming
L
Cheng
Guoping
G
Fan
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D058953:Neural Stem Cells / Q000502:physiology*; D009457:Neuroglia / Q000502:physiology
C000715535:Dnmt3a protein, mouse; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A