Chromatin remodeling and histone modification in the conversion of oligodendrocyte precursors to neural stem cells

Abstract

We showed previously that purified rat oligodendrocyte precursor cells (OPCs) can be induced by extracellular signals to convert to multipotent neural stem-like cells (NSLCs), which can then generate both neurons and glial cells. Because the conversion of precursor cells to stem-like cells is of both intellectual and practical interest, it is important to understand its molecular basis. We show here that the conversion of OPCs to NSLCs depends on the reactivation of the sox2 gene, which in turn depends on the recruitment of the tumor suppressor protein Brca1 and the chromatin-remodeling protein Brahma (Brm) to an enhancer in the sox2 promoter. Moreover, we show that the conversion is associated with the modification of Lys 4 and Lys 9 of histone H3 at the same enhancer. Our findings suggest that the conversion of OPCs to NSLCs depends on progressive chromatin remodeling, mediated in part by Brca1 and Brm.

Sox2 expression in breast tumours and activation in breast cancer stem cells

“…An area located between positions À528 and þ 238 from the transcription start site is considered as the core proximal promoter region (Miyagi et al, 2006). Additionally, an upstream enhancer centred between À3444 and À3833 has an active role in controlling expression of Sox2 in the reprogramming of oligodendrocyte precursors (Kondo and Raff, 2004) and in Figure 3 Sox2 is sufficient and necessary for sphere formation. (a) Transient transfection of Sox2 with pCAGSS control or pCAGSSSox2 expression vectors.…”

“…Recently, a possible implication of the transcription factor NF (nuclear factor)-kB has been proposed, although no direct regulation was reported (Liu et al, 2010). Kondo and Raff (Kondo and Raff, 2004) demonstrated that Sox2 reactivation in the conversion of oligodendrocyte precursors depends on the recruitment of the protein Brca1 to this enhancer, together with the chromatin remodelling protein Brm. These complexes have a critical role in the maintenance of the pluripotent state by regulating occupancy of pluripotency-related gene promoters (Kidder et al, Sox2 activation in breast cancer stem cells O Leis et al 2009).…”

Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells

“…Indeed, here we found that when OPCs were transformed into GIC-like cells, they lost their original features and acquired characteristics of NSCs. Although the detailed mechanism of the dedifferentiation caused by transformation remains to be elucidated, it is likely that epigenetic modification plays an important role, as we previously showed that epigenetic modification is involved in OPC reversion [16,37] and that activation of the Ras-signaling pathway induces alterations in epigenetic modification, chromatin structure, and gene expression [38][39][40][41][42]. As OPCs can be purified and cultured in serum-free medium with defined chemicals and mitogens, OPC transformation might be a good model for investigating the molecular mechanisms of dedifferentiation in tumorigenesis.…”

“…NSCs were prepared from embryonic day 13.5 p53-deficient mouse telencephalon and expanded as described previously [16]. For immunostaining, neurospheres were cultured on poly-D-lysine (15 lg/ml)-coated and fibronectin (1 lg/ml, Invitrogen, Carlsbad, CA, www.invitrogen.com)-coated eightwell chamber slides (Nalge Nunc, Rochester, NY, www.nalgenunc.com) in the presence of basic fibroblast growth factor (bFGF; 10 ng/ml) and epidermal growth factor (EGF; 10 ng/ ml) for up to 1 day.…”

“…For egfrvIII, the mouse 5 0 primer was 5 0 -ATGCGACCCT CCGGGACGG-3 0 , and the 3 0 primer was 5 0 -ATTCCGTTA CACACTTTGCGGC-3 0 . The primers for nestin, musashi1, sox2, olig1, olig2, mash1, and gapdh were described previously [16].…”