Epigenetic regulation of stemness maintenance in the neurogenic niches

Abstract

In the adult mouse brain, the subventricular zone lining the lateral ventricles and the subgranular zone in the dentate gyrus of the hippocampus are two zones that contain neural stem cells (NSCs) with the capacity to give rise to neurons and glia during the entire life of the animal. Spatial and temporal regulation of gene expression in the NSCs population is established and maintained by the coordinated interaction between transcription factors and epigenetic regulators which control stem cell fate. Epigenetic mechanisms are heritable alterations in genome function that do not involve changes in DNA sequence itself but that modulate gene expression, acting as mediators between the environment and the genome. At the molecular level, those epigenetic mechanisms comprise chemical modifications of DNA such as methylation, hydroxymethylation and histone modifications needed for the maintenance of NSC identity. Genomic imprinting is another normal epigenetic process leading to parental-specific expression of a gene, known to be implicated in the control of gene dosage in the neurogenic niches. The generation of induced pluripotent stem cells from NSCs by expression of defined transcription factors, provide key insights into fundamental principles of stem cell biology. Epigenetic modifications can also occur during reprogramming of NSCs to pluripotency and a better understanding of this process will help to elucidate the mechanisms required for stem cell maintenance. This review takes advantage of recent studies from the epigenetic field to report knowledge regarding the mechanisms of stemness maintenance of neural stem cells in the neurogenic niches.

Keywords: Neurogenesis, Neural stem cell, Epigenetics, Gene expression regulation, Chromatin modifications, DNA methylation

Core tip: Neural stem cells (NSCs) are capable of extensive self-renewal while preserving the ability to generate cell progeny that can differentiate into different cell types from the nervous system. Intrinsic mediators as well as extrinsic cues provided by the neurogenic niche (microenvironment where NSCs reside in vivo) are important for stem cell self-renewal and differentiation. Epigenetic changes, including alterations in DNA methylation, histone modifications and imprinting alter the way a gene interacts with the cell transcribing machinery, turning genes “on” or “off”. These heritable changes must be reversible and context-dependent being responsible of stem cell plasticity.