Abstract
DNA methylation and demethylation at CpG di-nucleotide sites plays important roles in cell fate specification of neural stem cells (NSCs). We have previously reported that DNA methyltransferases, Dnmt1and Dnmt3a, serve to suppress precocious astrocyte differentiation from NSCs via methylation of astroglial lineage genes. However, whether active DNA demethylase also participates in astrogliogenesis remains undetermined. In this study, we discovered that a Ten-eleven translocation (Tet) protein, Tet2, which was critically involved in active DNA demethylation through oxidation of 5-Methylcytosine (5mC), drove astrocyte differentiation from NSCs by demethylation of astroglial lineage genes including Gfap. Moreover, we found that an NSC-specific bHLH transcription factor Olig2 was an upstream inhibitor for Tet2 expression through direct association with the Tet2 promoter, and indirectly inhibited astrocyte differentiation. Our research not only revealed a brand-new function of Tet2 to promote NSC differentiation into astrocytes, but also a novel mechanism for Olig2 to inhibit astrocyte formation.
Highlights
Neural stem cells (NSCs) are self-renewing, multipotent stem cells that possess both the ability to proliferate and self-renew and to differentiate into three major cell lineages in the central nervous system (CNS), namely neurons, astrocytes, and oligodendrocytes[1]
The fact that Dnmt3a is required to keep the Gfap proximal promoter in a highly methylated state in undifferentiated embryonic day 11 (E11) NSCs suggested that this locus is under the dynamic active methylation and demethylation controls, and its methylation could not be maintained by Dnmt[1]
To explore the potential active demethylation control of the astroglial lineage gene Gfap, we examined expression levels of Teneleven translocation (Tet)[1, 2], and 3 in undifferentiated NSCs, fully differentiated astrocytes, and neurons isolated from E14/15 embryonic mouse cortex (Fig. 1c)
Summary
Neural stem cells (NSCs) are self-renewing, multipotent stem cells that possess both the ability to proliferate and self-renew and to differentiate into three major cell lineages in the central nervous system (CNS), namely neurons, astrocytes, and oligodendrocytes[1]. Lineage differentiation into these three cell types is tightly regulated in a spatial and temporal-specific manner[2,3]. Both in vivo and in vitro, NSCs first differentiate into neurons glial cells[3,4].
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