title: DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling.
abstract: 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.
authors: Department of Human Genetics, University of California at Los Angeles, 695 Charles Young Drive South, Los Angeles, CA 90095, USA. gfan@mednet.ucla.edu
authors: Guoping
authors: G
authors: Fan
authors: Keri
authors: K
authors: Martinowich
authors: Mark H
authors: MH
authors: Chin
authors: Fei
authors: F
authors: He
authors: Shaun D
authors: SD
authors: Fouse
authors: Leah
authors: L
authors: Hutnick
authors: Daisuke
authors: D
authors: Hattori
authors: Weihong
authors: W
authors: Ge
authors: Yin
authors: Y
authors: Shen
authors: Hao
authors: H
authors: Wu
authors: Johanna
authors: J
authors: ten Hoeve
authors: Ke
authors: K
authors: Shuai
authors: Yi E
authors: YE
authors: Sun
mesh_terms: 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
chemical_list: 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