Nuclear factor I/A coordinates the timing of oligodendrocyte differentiation/maturation via Olig1 promoter methylation

Katsunori Semi,Tsukasa Sanosaka,Kinichi Nakashima,Masakazu Namihira

doi:10.4308/hjb.25.2.70

Abstract

Transcription factors (TFs) and epigenetic modifications function cooperatively to regulate various biological processes such as cell proliferation, differentiation, maturation, and metabolism. TF binding to regulatory regions of target genes controls their transcriptional activity through alteration of the epigenetic status around the binding regions, leading to transcription network formation regulating cell fates. Although nuclear factor I/A (Nfia) is a well-known TF that induces demethylation of astrocytic genes to confer astrocytic differentiation potential on neural stem/precursor cells (NS/PCs), the epigenetic role of NFIA in oligodendrocytic lineage progression remains unclear. Here, we show that oligodendrocyte differentiation/maturation is delayed in the brains of Nfia-knockout (KO) mice, and that NFIA-regulated DNA demethylation in NS/PCs plays an important role in determining the timing of their differentiation. We further demonstrate that the promoter activity of the oligodendrocyte transcription factor 1 (Olig1) gene, involved in oligodendrocyte differentiation/maturation, is suppressed by DNA methylation, which is in turn regulated by Nfia expression. Our results suggest that NFIA controls the timing of oligodendrocytic differentiation/maturation via demethylation of cell-type-specific gene promoters.

Highlights

Epigenetic modifications, such as histone modifications and DNA methylation, are deeply involved in the regulation of various cellular processes, including transcription, imprinting, and cell differentiation (Feng et al 2007)
We reported that neural stem/precursor cells (NS/PCs) isolated from E14.5 nuclear factor I/A (Nfia)-KO mouse forebrains showed impaired astrocyte differentiation when treated with the astrocyte-inducing cytokine leukemia inhibitory factor (LIF) (Namihira et al 2009)
Whereas WT NS/PCs differentiated into GFAP-positive astrocytes, Nfia-KO NS/PCs showed no GFAP expression, with most cells still expressing Nestin, a marker for undifferentiated Neural stem cells (NSCs) (Figure 1b). This result shows that 4-day culture with basic fibroblast growth factor (bFGF) is not sufficient for Nfia-KO NS/PCs to acquire the potential for astrocyte differentiation, likely because the Gfap promoter is still highly methylated (Namihira et al 2009)

Summary

Introduction

Epigenetic modifications, such as histone modifications and DNA methylation, are deeply involved in the regulation of various cellular processes, including transcription, imprinting, and cell differentiation (Feng et al 2007). DNA methylation is maintained by DNA methyltransferases (DNMTs) and is heritable to sister cells. In the process of development from an early embryo, DNA methylation patterns are constructed and adjusted to suit each differentiated cell type. It is generally known that methylation of gene promoter regions suppresses transcription by preventing the binding of transcription factors (TFs) or recruiting repressor complexes involving methylated-DNA-binding proteins (Tate and Bird 1993; Lister and Ecker 2009). During central nervous system (CNS) development, astrocyte differentiation is strongly influenced by DNA methylation.

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