Genetics and Epigenetics in Adult Neurogenesis

Abstract

The cellular basis of adult neurogenesis is neural stem cells residing in restricted areas of the adult brain. These cells self-renew and are multipotent. The maintenance of "stemness" and commitment to differentiation are tightly controlled by intricate molecular networks. Epigenetic mechanisms, including chromatin remodeling, DNA methylation, and noncoding RNAs (ncRNAs), have profound regulatory roles in mammalian gene expression. Significant advances have been made regarding the dynamic roles of epigenetic modulation and function. It has become evident that epigenetic regulators are key players in neural-stem-cell self-renewal, fate specification, and final maturation of new neurons, therefore, adult neurogenesis. Altered epigenetic regulation can result in a number of neurological and neurodevelopmental disorders. Here, we review recent discoveries that advance our knowledge in epigenetic regulation of mammalian neural stem cells and neurogenesis. Insights from studies of epigenetic gene regulation in neurogenesis may lead to new therapies for the treatment of neurodevelopmental disorders.

Figure 1.

Four major categories of epigenetic mechanisms: histone modification, chromatin remodeling, DNA methylation, and noncoding RNAs (ncRNAs). The dynamic nature of epigenetic mechanisms offers an important layer of gene regulation, controlling the multiple steps of adult neurogenesis in response to environmental signals.

Figure 2.

Cross talk between transcription factors and epigenetic mechanisms to control neurogenesis. Transcription factors (TFs) regulate the expression of microRNAs (miRNAs), which, in turn modulate various downstream targets to control the different stages of adult neurogenesis. This extensive cross-regulation between TFs, miRNAs, and their messenger RNA (mRNA) targets is essential to maintain homeostasis of neural stem/progenitor cells (NSPCs) and the production of new neurons in the adult mammalian brain. NSC, Neural stem cell; BDNF, brain-derived neurotrophic factor; CREB, cAMP-response element-binding protein; CBP, CREB-binding protein; MBD, methyl-binding domain.

Figure 3.

Studies of epigenetic regulation in experimental models. These studies may have a significant impact on the understanding and treatment of human diseases. Insights from animal and in vitro models may guide the development of effective therapeutic treatments (e.g., stem-cell transplantation) or drugs (e.g., inhibitors of histone-modifying enzymes, so-called “epi-drugs”) for human neurodevelopmental disorders.