16 Genetics and Epigenetics in Adult Neurogenesis

Abstract

Chromatin structure and function are dynamically regulated in stem cells of the brain, which serve as an important paradigm for understanding the regulatory mechanisms that transduce physiological and pathophysiological signals to the stem cell genome. In the adult vertebrate brain, the production of newborn neurons from stem cells (neurogenesis) takes place in discrete proliferation zones (niches), such as the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus (Gage 2000). A variety of signals, ranging from excitation due to locally released neurotransmitters to systemic factors or drugs that cross the blood-brain barrier, converge upon clusters of neuronal stem/progenitor cells (NSCs) residing in these niches, which are intimately associated with the cerebral microvasculature. Balanced control of self-renewal, differentiation, and survival of NSCs produces new neurons and glial cells necessary for functional homeostasis of the brain and also has an important role in brain function such as memory and learning. Moreover, as potential cancer stem cells, NSCs are suspected to be the root of brain malignancies such as glioblastoma multiforme. To become neurons, NSCs require coordinated changes in the pattern of gene expression, primarily regulated at the level of gene transcription. Epigenetic chromatin remodeling has emerged as a fundamental higher-order mechanism for fine-tuning and coordinating gene expression during neurogenesis. Important aspects of brain function such as synaptic plasticity are also governed by chromatin-remodeling enzymes, cell-type-specific transcriptional regulators, and small regulatory noncoding RNAs. Thus, signaling to the genome through diverse epigenetic regulatory mechanisms...