Sirt2 epigenetically down-regulates PDGFRα expression and promotes CG4 cell differentiation

Abstract

We have previously found that Sirt2 enhanced the outgrowth of cellular processes and MBP expression in CG4 cells, where Sirt2 expression is suppressed by transcription factor Nkx2.2. However, the detailed mechanism of Sirt2 facilitating oligodendroglial cell differentiation remained unclear. In the present study, we observed that Sirt2 partially translocated into the nuclei when CG4 cells were induced to differentiate. Sirt2 was detected at the CpG island of PDGFRα promoter via ChIP assay during the cells differentiation process rather than during the state of growth. Sirt2 deacetylated protein(s) bound to the promoter of PDGFRα and simultaneously appeared to facilitate histone3 K27 tri-methylation, both of which are suppressive signatures on gene transcription activation. In bisulfate assay, we identified that Sirt2 significantly induced DNA methylation of PDGFRα promoter compared with the control. Consistently, Sirt2 overexpression down-regulated PDGFRα expression in CG4 cells. The knock-down of PDGFRα or Sirt2 over-expression repressed cell proliferation, but knock-down of Sirt2 promoted cell proliferation. Taken together, Sirt2 translocated into the nuclei while the cells initiated a differentiation process, facilitating CG4 cell differentiation partially through epigenetic modification and suppression of PDGFRα expression. The repression of PDGFRα expression mediated by Sirt2 appeared to facilitate a transition of cellular processes, i.e. from a proliferating progenitor state to a post-mitotic state in CG4 cells.

Global DNA methylation pattern involved in the modulation of differentiation potential of adipogenic and myogenic precursors in skeletal muscle of pigs

“…Different from functions of the above genes in myogenesis, PDGFRα + mesenchymal progenitors were the major contributor to ectopic fat formation in skeletal muscle [ 37 ], and embryonic adipose progenitor cells without PDGFRα would undergo fate change from adipogenic to fibrotic lineage [ 64 ]. Although DNA methylation-induced PDGFRα and FGFR2 silencing has been reported in CG4 cells [ 65 ] or primary human pituitary adenomas [ 66 ], the role of DNA methylation in regulating the expression level of these co-different genes and their effects on myogenesis or adipogenesis still remains unclear. Unlike the well-known functions of the above genes in ectopic fat accumulation and skeletal muscle development, the function of CNCNA2D2 in relation to skeletal muscle development and homeostasis has been sparsely described in previous studies.…”

Microglia Impede Oligodendrocyte Generation in Aged Brain

“… 78 Nevertheless, these studies are based on the inhibition of Stat1 pathway in all somatic cells, the influence of Stat1 pathway regulation on remyelination specifically in microglia needs further study. Although the factors such as Pdgfa and Pdgfb secreted by microglia and receptor Pdgfra, Gpr37l1 on OPCs can hinder the differentiation of OPCs, 43 , 48 functional changes revealed by GO analysis in aged OPCs showed no hint of their roles. However, our analysis did not exclude their possible influences and more efforts are needed for further investigation.…”

“…37,43 Apoe, App, Pdgfa, Pdgfb and Sdc4 were included in the myelin impediment group (Figure 6B) due to their potential hindrance in OPC differentiation. 48,49 Beneficial cytokines Vegfb and Igf1 did not show significantly high expression in activated microglia (Figure 6B). Subsequently, we attempted to identify several regulatory factors that can upregulate those factors in the myelin promotion group and down-regulate those factors in the myelin impediment group.…”

Sirt2 promotes white matter oligodendrogenesis during development and in models of neonatal hypoxia

“…Cytoplasmic Sirt2 deacetylates multiple proteins, including alpha-tubulin in cultured OPCs 19 and HeLa cells 20 , as well as the polarity protein Par-3 in Schwann cells 21 . Sirt2 also suppressed PDGFRα expression after translocation to the nucleus, promoting differentiation of the CG4 glial cell line 22 . In addition, a recent study found that Sirt2 is delivered to axons from OL to promote mitochondrial ATP production 23 .…”