p27^Kip1 Enhances myelin basic protein gene promoter activity

Abstract

The process of oligodendrocyte differentiation is a complex event that requires cell cycle withdrawal, followed by the activation of a specific transcriptional program responsible for the synthesis of myelin genes. Because growth arrest precedes differentiation, we sought to investigate the role of cell cycle molecules in the activation of myelin gene promoters. We hypothesized that the cell cycle inhibitor p27(Kip1), which is primarily responsible for arresting proliferating oligodendrocyte progenitors, may be involved in the transcriptional regulation of myelin genes. In agreement with this hypothesis, overexpression of p27(Kip1) in the CG4 cell line, but not in 3T3 fibroblasts, enhances the expression of luciferase driven by the myelin basic protein (MBP) promoter. Interestingly, this effect is specific for p27(Kip1); overexpression of other cell cycle inhibitors had no effect. Additionally, this effect is independent of halting the cell cycle; treatment with the cell cycle blocker roscovitine did not affect MBP promoter usage. We conclude that p27(Kip1) contributes to oligodendrocyte differentiation by regulating transcription of the MBP gene.

Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1

“…An alternative possibility is that some cell-cycle genes might affect the transcriptional machinery after the cells have exited from the cell cycle. This hypothesis is supported by evidence that links p27Kip to transcriptional activation of myelin genes (Miskimins et al, 2002) and p21Cip to oligodendrocyte differentiation independent of its role in cell-cycle regulation (Zezula et al, 2001). More recent studies further support an alternative role for the cell-cycle related molecule p57Kip2 as a modulator of the transcriptional network regulating oligodendrocyte differentiation (Dugas et al, 2007).…”

“…Because decreased expression of transcriptional inhibitors is important for the timing of progenitor differentiation and for myelin gene expression, we searched for a mechanism that regulates the expression levels of the inhibitors themselves. Studies from our group have identified that global deacetylation of histone H 3 is crucial for the decrease in transcriptional inhibitors of differentiation and that this occurs during the transition between cell-cycle exit and differentiation onset (Marin-Husstege et al., 2002;Shen et al, 2005). Therefore we proposed that global histone deacetylation is responsible for the decreased transcription of differentiation inhibitors.…”

“…During the last decade identification of the intrinsic mechanisms that underlie cellular differentiation in the developing CNS has been the subject of intense investigation. One line of investigation has focused on the role of chromatin modifiers as intrinsic modulators of fate choice during brain development (Ballas et al, 2001;Marin-Husstege et al, 2002;Ballas et al, 2005;Fan et al, 2005;Colvis et al, 2005;Miller and Gauthier, 2007;Lessard et al, 2007;He et al, 2007;Liu et al, 2007;Shen and Casaccia-Bonnefil, 2007). Among the epigenetic factors that modulate brain development, different groups have focused on post-translational modification of the histone tails, switching histone variants, ATP-remodeling complexes and microRNAs (Seo et al, 2005;Matsumoto et al, 2006;Cao et al, 2006).…”

“…By analogy to the astrocytic and neuronal lineages it has been suggested that timing of differentiation might be achieved by counteracting the enzymatic activities in the repressive complexes. However, pharmacological inhibition of HDACs in vitro prevents rather than facilitates the expression of myelin genes (Marin-Husstege et al, 2002). In addition, systemic administration of HDAC inhibitors to developing rat pups alters the timing of oligodendrocyte differentiation and delays myelination (Shen et al, 2005).…”

Post-Translational Modifications of Nucleosomal Histones in Oligodendrocyte Lineage Cells in Development and Disease

“…The importance of cell-cycle inhibitors in oligodendrocyte differentiation was further suggested by reports of alternative biological functions for these molecules. P27Kip, for instance, was identified as part of a transcriptional complex activating the MBP promoter (Miskimins et al 2002), as well as part of a complex with specific RNA-binding proteins like Qki (Larocque et al 2005). Despite these exciting findings, overexpression of cell-cycle inhibitors per se was not sufficient to induce differentiation (Tikoo et al 1998;Tang et al 1999) and suggested that additional events must be responsible for the differentiation of progenitors into mature oligodendrocytes.…”