DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling
2005
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.
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