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Home arrow Health arrow DNA Modifications in the Brain. Neuroepigenetic Regulation of Gene Expression
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FUNDAMENTAL BRAIN DEVELOPMENT

In mammals, the nervous system develops from ectoderm, the surface layer of the gas- trula. Later in development, the mesoderm gives rise to the notochord, which releases the organizer proteins noggin and chordin. These proteins block the suppressive effects

Copyright © 2017 Elsevier Inc.

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DNA Modifications in the Brain ISBN 978-0-12-801596-4

http://dx.doi.org/10.1016/B978-0-12-801596-4.00003-4

Genomic view of distinct histone marks and cytosine modifications with schematic interplay

Figure 3.1 Genomic view of distinct histone marks and cytosine modifications with schematic interplay. Cytosines (C) are methylated by DNA methyltransferases (Dnmts) to 5-mC (CH3-C), which are oxidized to 5-hydroxymethylcytosine (5hmC) (CH2OH-C) by Ten-eleven translocations (TETs). TETs can oxidize the 5hmC to the 5-formylcytosine (5fC) (CHO-C) and further to 5-carboxylcytosine (5caC) (COOH-C). Both 5fC and 5caC are excised by thymine DNA glycosylase (TDG), eventually converted back to C. Genetic elements such as enhancers and promoter are defined by the histone marks and transcription factors showing characteristic C methylation. The relative enrichment pattern of each C methylation interplay element shows specific enrichments on certain genetic elements, indicating peculiar role in epigenetic regulation of gene activity. UTR, untranslated region.

of bone morphogenetic protein (BMP), allowing the ectoderm to form the neural plate, then the neural tube, and eventually the ventricular system, where neurogenesis proceeds within the walls of the tube to form the CNS, including the brain and spinal cord (Butler & Hodos, 2005; Siegel & Sapru, 2015). The neural plate and neural tube are composed of a single layer of neuroepithelial cells, which can be considered as neural stem cells (NSCs) (Gotz & Huttner, 2005). After closure of the neural tube, neuroepithelial cells undergo asymmetric division to generate a daughter stem cell, plus a more differentiated cell, such as a radial glial (RG) cell or a neuron (Gotz & Huttner, 2005; Huttner & Brand, 1997). With the switch to neurogenesis, all neuroepithelial cells undergo a transformation and give rise to RG cells. RG cells are fate-restricted progenitors, which can either generate nascent neurons by symmetric division or undergo selfrenewal by asymmetric division (Gotz & Huttner, 2005; Yao & Jin, 2014). Both neuroepithelial cells and RG cells can generate a type of intermediate neuron progenitor cell, basal progenitors (BPs), which can generate neurons by symmetrical division (Gotz & Huttner, 2005; Haubensak, Attardo, Denk, & Huttner, 2004; Noctor, Martinez- Cerdeno, Ivic, & Kriegstein, 2004). RGs also generate astrocytes and oligodendrocytes. Some RGs remain quiescent in the subventricular zone (SVZ) and work as NSCs in adult neurogenesis (Yao & Jin, 2014).

Unlike embryonic neurogenesis, adult neurogenesis is thought to be restricted to just two regions: the SVZ of the lateral ventricle and the dentate gyrus subgranular zone (SGZ) of the hippocampus. The adult SVZ harbors radial glia-like cells (B cells), which are the SVZ stem cells. Proliferating B cells give rise to transient amplifying cells (C cells), which in turn generate neuroblasts (A cells). Through a tube formed by astrocytes, A cells form a chain, called the rostral migratory stream, and migrate toward the olfactory bulb, where the A cells are converted to different subtypes of mature neurons (Alvarez-Buylla & Lim, 2004; Ming & Song, 2011;Yao & Jin, 2014). In the SGZ, radial glia-like cells (type I cells) and nonradial precursor cells (type II cells) work as neural progenitors in the DG. These cells produce intermediate progenitors, which in turn generate neuroblasts. Neuroblasts migrate into the inner granule cell (GC) layer and differentiate into dentate GCs in the hippocampus (Ming & Song, 2011; Zhao, Deng, & Gage, 2008).

During brain development and neurogenesis (Fig. 3.2), both identity and differentiation potential are determined by orchestration between extracellular signals, such as BMP and Sonic Hedgehog (Butler & Hodos, 2005), and an intracellular network, such as transcription factors Pax6 (Balmer et al., 2012) and Dlx2 (Lim et al., 2009). Epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodeling, and noncoding RNA, have been implicated in determining the DNA and histone accessibility of critical genes and in fine-tuning the expression of transcription factors. For example, Gadd45b is required for activity-induced DNA demethylation of specific promoters and the expression of corresponding genes critical for adult neurogenesis, among them brain-derived neurotrophic factor (Bdnf) and fibroblast growth factor-1 (Fgf-1) (Ma et al., 2009). Over the years, there have been interesting studies that have provided new insight into prospective epigenetic regulatory mechanisms in the nervous system. In particular, given the highly enriched level of 5-hmC in brain relative to many other tissues and cell types (for example, in Purkinje cells of the cerebellum, 5-hmC is approximately 40% as abundant as 5-mC), here we highlight the potential functional roles of this cytosine modification, and others, in brain development.

 
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