DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling.
DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The developmentally regulated demethylation of astrocyte marker genes as well as genes encoding the crucial components of the gliogenic JAK-STAT pathway is accelerated in Dnmt1-/- NPCs. Through a chromatin remodeling process, demethylation of genes in the JAK-STAT pathway leads to an enhanced activation of STATs, which in turn triggers astrocyte differentiation. Our study suggests that during the neurogenic period, DNA methylation inhibits not only astroglial marker genes but also genes that are essential for JAK-STAT signaling. Thus, demethylation of these two groups of genes and subsequent elevation of STAT activity are key mechanisms that control the timing and magnitude of astroglial differentiation.
Fan
Guoping
G
Department of Human Genetics, University of California at Los Angeles, 695 Charles Young Drive South, Los Angeles, CA 90095, USA. gfan@mednet.ucla.edu
Martinowich
Keri
K
Chin
Mark H
MH
He
Fei
F
Fouse
Shaun D
SD
Hutnick
Leah
L
Hattori
Daisuke
D
Ge
Weihong
W
Shen
Yin
Y
Wu
Hao
H
ten Hoeve
Johanna
J
Shuai
Ke
K
Sun
Yi E
YE
D000818:Animals; D001253:Astrocytes / Q000166:cytology*; D001483:Base Sequence; D001921:Brain / Q000196:embryology; D002454:Cell Differentiation; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D017931:DNA Primers; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection
D017931:DNA Primers; D015534:Trans-Activators; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000619382:Dnmt1 protein, rat