Epigenetic regulation of self‐renewal and fate determination in neural stem cells

Abstract

Differentiation and self-renewal are two primary properties that characterize stem cells. Differentiation of neural stem/precursor cells (NSPCs) gives rise to multiple neural lineages, including neurons, astrocytes, and oligodendrocytes. Self-renewal, by definition, signifies the progressive growth of cells, while preserving an undifferentiated state. A large number of interdependent factors, including transcription factors, epigenetic control, and micro-RNA regulators, modulate these opposing processes without disrupting the regular neural network. The epigenetic modification of developmental genes, including alterations in DNA methylation, histone modifications, polycomb gene group and noncoding RNA expression, which are passed on through successive cell divisions, has proved to be one of the major mechanisms determining the fate of neural stem cells. Here, we review the diverse epigenetic pathways that decide whether NSPCs undergo proliferation or differentiation into different neuronal cell lineages.

Enhanced differentiation of neural progenitor cells into neurons of the mesencephalic dopaminergic subtype on topographical patterns

“…Hence the hippocampal origin of mNPCs may limit their potential in developing into mesencephalic neurons. In particular, the epigenetic differences between the subventricular zone and hippocampal neurons account for differences in miRNA regulation of neurogenesis [41].…”

Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease

“…Individual mechanisms of DNA and histone modifications and non-coding RNAs are responsible for these changes in gene expression patterns. In addition, these mechanisms interact and are capable of influencing each other, forming a complex network of epigenetic and non-epigenetic regulation of adult neurogenesis [16,53,54]. Several epigenetic mechanisms that control self-renewal and differentiation of NSCs have been identified and will be discussed below.…”

“…Indirectly, the binding affinity of other transcriptional regulators, including co-activator and co-repressor factors and complexes is modulated by DNA methylation. Together, de novo methylation and maintenance of methylation marks, either directly or indirectly affecting gene expression, are capable of regulating sequential steps of adult neurogenesis [51,54]. …”

“…This family of proteins responds to changes in the environment by releasing gene repression at specific genes through the promotion of DNA demethylation [16,54,87]. Gadd45b is important specifically for the sequential steps of activity-induced neurogenesis in the adult hippocampus.…”

“…Moreover, deficits in dendritic growth were observed in Gadd45b knockout mice, indicating that Gadd45b is important for neuronal maturation [81]. Methylated DNA immunoprecipitation (MeDIP) analysis revealed that Gadd45b is necessary for demethylation at different genes encoding growth factors involved in neurogenesis, including FGF1 [81], which regulates self-renewal and proliferation of NSCs similar to FGF2 [54]. These results indicate that Gadd45b is an immediate early gene expressed in mature neurons upon neural activity that subsequently regulates growth factor expression through DNA demethylation.…”