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Proteins in DNA Methylation and Their Role in Neural Stem Cell Proliferation and Differentiation Jiaqi Sun1* , Junzheng Yang1, Xiaoli Miao1, Horace H

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Proteins in DNA Methylation and Their Role in Neural Stem Cell Proliferation and Differentiation Jiaqi Sun1* , Junzheng Yang1, Xiaoli Miao1, Horace H Sun et al. Cell Regeneration (2021) 10:7 https://doi.org/10.1186/s13619-020-00070-4 REVIEW Open Access Proteins in DNA methylation and their role in neural stem cell proliferation and differentiation Jiaqi Sun1* , Junzheng Yang1, Xiaoli Miao1, Horace H. Loh1, Duanqing Pei1,2,3,4,5 and Hui Zheng1,2,3,4* Abstract Background: Epigenetic modifications, namely non-coding RNAs, DNA methylation, and histone modifications such as methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation play a significant role in brain development. DNA methyltransferases, methyl-CpG binding proteins, and ten-eleven translocation proteins facilitate the maintenance, interpretation, and removal of DNA methylation, respectively. Different forms of methylation, including 5-methylcytosine, 5-hydroxymethylcytosine, and other oxidized forms, have been detected by recently developed sequencing technologies. Emerging evidence suggests that the diversity of DNA methylation patterns in the brain plays a key role in fine-tuning and coordinating gene expression in the development, plasticity, and disorders of the mammalian central nervous system. Neural stem cells (NSCs), originating from the neuroepithelium, generate neurons and glial cells in the central nervous system and contribute to brain plasticity in the adult mammalian brain. Main body: Here, we summarized recent research in proteins responsible for the establishment, maintenance, interpretation, and removal of DNA methylation and those involved in the regulation of the proliferation and differentiation of NSCs. In addition, we discussed the interactions of chemicals with epigenetic pathways to regulate NSCs as well as the connections between proteins involved in DNA methylation and human diseases. Conclusion: Understanding the interplay between DNA methylation and NSCs in a broad biological context can facilitate the related studies and reduce potential misunderstanding. Keywords: DNA methylation, Neural stem cells, DNA methyltransferases, Methyl-CpG binding proteins, Ten-eleven translocations, Vitamin C Background RNAs, and histone modifications are three predominant Epigenetics, the study of heritable changes in gene func- mechanisms. Particularly, in mammalian DNA, the prin- tions without changes in the actual genetic or underlying cipal modification is methylated cytosine, which is cata- DNA sequence mechanisms (Bird 2007), is a fundamen- lyzed by a family of DNA methyltransferase enzymes tal mechanism in modulating gene expression in a par- (DNMTs) (Goll and Bestor 2005) and predominantly oc- ticular cell type during development. DNA methylation, curs in CpG dinucleotide sequences to generate 5- one of the main epigenetic modifications, non-coding methylcytosine (5-mC) on the pyrimidine ring (Zhu 2009). DNA methylation in terminally differentiated cells * Correspondence: [email protected]; [email protected] was believed to be irreversible until the discovery of ten- 1Bioland Laboratory (Guangzhou Regenerative Medicine and Health eleven translocation (TET) enzymes in 2009 (Pastor Guangdong Laboratory), #188 Kaiyuan Ave., Science City, Huangpu District, Guangzhou 510700, China et al. 2013). TET enzymes, identified as key players in Full list of author information is available at the end of the article active DNA demethylation process, can convert 5-mC © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sun et al. Cell Regeneration (2021) 10:7 Page 2 of 12 into 5-hydroxymethylcytosine (5-hmC) (Tahiliani et al. somatic cells (Law and Jacobsen 2010). However, the 2009; Ito et al. 2010) and subsequently into 5- classification is not tightly restricted. Limited evidence formylcytosine (5-fC) and 5-carboxylcytosine (5-caC) suggests the presence of de novo activity of DNMT1 (Ito et al. 2011). The functions of TET proteins in brain (Okano et al. 1998; Yarychkivska et al. 2018; Arand et al. development attract much attention because the mam- 2012), but the overall evidence was not immediately malian brain has the highest abundance of 5-hmC clear. In 2018, Zhu’s group found the first systematic among all the tissues investigated thus far (Kriaucionis evidence confirming that DNMT1 functions as a de and Heintz 2009; Globisch et al. 2010). novo methyltransferase in vivo (Li et al. 2018). It has In mammalian embryogenesis, central nervous system been reported that inhibiting DNMT1-mediated de novo (CNS) development begins with the induction of neu- methylation by Stella is important for establishing DNA roectoderm, which forms the neural plate and then in- methylation pattern during oogenesis (Li et al. 2018). vaginates to generate the neural tube. Neural stem cells Utilizing a “DNMT1-only” mouse embryonic stem cell (NSCs) arise from neuroepithelial cells and the radial line, a collaborative study by Xie’s and Zhu’s groups glia lining the neural tubes and differentiate into three found that weak de novo methylation activity and imper- major cell types in the CNS in a temporally defined se- fect maintenance methylation activity of DNMT1 can quence, with neurons appearing first, followed by astro- lead to spontaneous DNA methylation mutations (epi- cytes, and oligodendrocytes (Temple 2001; Kriegstein mutations), which tend to be repaired by neighbor- and Alvarez-Buylla 2009). After the completion of the guided correction based on the de novo and mainten- initial embryonic development, multipotent NSCs are ance activities of DNMT1 in turn (Wang et al. 2020a). largely restricted to two germinal zones in rodent model, Additionally, the researchers found that the de novo and namely the subgranular zone (SGZ) of the dentate gyrus maintenance activities of DNMT1 vary in different gen- in the hippocampus and the subventricular zone (SVZ) ome regions, such as the enrichment of H3K9me2/3 along the lateral ventricular wall (Kempermann and areas with higher de novo activity and CpG islands with Gage 1999; Ming and Song 2011). In a mouse study, lower maintenance and de novo activities, thereby pro- adult hippocampal neurogenesis, which shares embry- viding a new mechanism for maintaining different onic dentate neural progenitors, was found to be a con- methylation levels in different regulatory sequences of tinuous process from development (Berg et al. 2019). the genome. Except for CpG methylation, other non- NSCs in the adult CNS sparkle the field that these pre- CpG sequences containing cytosine (CpA/C/T) can be served cells can be harnessed to repair injured or dis- methylated (hereafter referred to as mCpH) and have eased brain. Therefore, the regulation of the been found in embryonic stem cells (Lister et al. 2009; proliferation and differentiation of NSCs is an important Ramsahoye et al. 2000) and neurons (Guo et al. 2014). area of research. Significant advances to identify the dy- Unlike most mCpG, mCpH is established during postna- namic roles of DNA methylation in brain development tal neuronal maturation in both the mouse and human have been made. In this review, we highlight DNA brains. de novo methyltransferase DNMT3A has been methylation and DNA demethylation, focusing on the shown to induce non-CpG methylation (Ramsahoye modulation of the proliferation and differentiation of et al. 2000). A study of DNA methylation at single-base NSCs. resolution in human has revealed that the highly con- served non-CpG methylation accumulates in neurons DNA methylation in NSC proliferation and but not in glia during postnatal development, a critical differentiation period of synaptogenesis and neural circuit maturation DNA methyltransferases (Lister et al. 2013). The growing knowledge on non-CpG DNA methylation is a major epigenetic mechanism for methylation can shed new light on the function of DNA gene inactivation; it serves as the basis of silenced X methylation in modulating brain development and chromosome and the establishment of parental-specific plasticity. imprints during gametogenesis (Jaenisch and Bird 2003; Neurogenesis precedes astrogenesis in embryonic Reik 2007). DNA methylation is catalyzed by a family of brain development. Therefore, inhibiting the expression DNA methyltransferases (DNMTs), including DNMT1, of genes critical for astrocytes in NSCs is a key step in DNMT3A, and DNMT3B (Goll and Bestor 2005). determining the neuronal differentiation of these cells. DNMT3A and DNMT3B are de novo methyltransfer- DNMT1 is vital in the switch from neurogenesis to glio- ases, which are responsible for the covalent addition of a genesis during this process. DNMT1 deficiency in
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