Watch the epigenetics video from PBS. Begin your paper by defining epigenetics in your own words and discussing your reaction to the video. (you can choose whatever disease) Interview your family mem

Review Article Epigenetic Regulations in Neural Stem Cells and Neurological Diseases Hang Zhou, 1,2 Bin Wang, 2Hao Sun, 3Xingshun Xu ,1,2 and Yongxiang Wang 3 1Department of Neurology, The Second Aﬃliated Hospital of Soochow University, Suzhou, China2Institute of Neuroscience, Soochow University, Suzhou, China3Department of Orthopedics, Clinical Medical School, Yangzhou University, Northern Jiangsu People ’s Hospital, Yangzhou 225001, China Correspondence should be addressed to Xingshun Xu; [email protected] and Yongxiang Wang; [email protected] Received 4 November 2017; Accepted 8 January 2018; Published 18 March 2018 Academic Editor:

Yujing Li Copyright © 2018 Hang Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Among the regulatory mechanisms of the renewal and di ﬀerentiation of neural stem cells, recent evidences support that epigenetic modi ﬁcations such as DNA methylation, histone modi ﬁcation, and noncoding RNAs play critical roles in the regulation on the proliferation and di ﬀerentiation of neural stem cells. In this review, we discussed recent advances of DNA modiﬁ cations on the regulative mechanisms of neural stem cells. Among these epigenetic modiﬁ cations, DNA 5-hydroxymethylcytosine (5hmC) modi ﬁcation is emerging as an important modulator on the proliferation and di ﬀerentiation of neural stem cells. At the same time, Ten-eleven translocation (Tet) methylcytosine dioxygenases, the rate-limiting enzyme for the 5-hydroxymethylation reaction from 5-methylcytosine to 5-hydroxymethylcytosine, play a critical role in the tumorigenesis and the proliferation and di ﬀerentiation of stem cells. The functions of 5hmC and TET proteins on neural stem cells and their roles in neurological diseases are discussed. 1. Introduction Human beings are developed from a fertilized egg into a complete individual; during the whole process, a series of precise regulations on the development are included, such as gene expression and gene silence [1], transcriptional regu- lation [2], posttranscriptional regulation [3], hormone regulation [4], chromosome behavior regulation [5], and apoptosis [6]. For these di ﬀerent regulative pathways, their target cells are embryonic stem cells (ESCs). ESCs are totipo- tent stem cells that had a capability to proliferate and di ﬀer- entiate into appropriate lineages to form specialized cells and organs and play a central role in the developmental process [7]. Due to the powerful plasticity and potential of ESCs as a high potential cell replacement therapy for many diseases, stem cells are considered to have an appreciable translational prospect in the ﬁeld of regenerative medicine [8]. Except for ESCs at the embryonic stage of the development, adult stem cells (ASCs) exist in di ﬀerent tissues at the adult stage of the development [9]. ASCs are often in a resting state in individuals and exhibit di ﬀerent potentials of regeneration and di ﬀerentiation under pathological conditions or special incentives. Reynolds and Weiss ﬁrst found that the neurons isolated from the striatum of the adult mouse brain could proliferate and di ﬀerentiate in vitro with epidermal growth factors [9], indicating the existence of neural stem cells (NSCs) in the mature nervous system. They also demon- strated that NSC has the ability to self-renew and di ﬀerenti- ate into other types of cells like neurons, astrocytes, and oligodendrocytes under many conditions such as growth fac- tors, neurotransmitters, hormones, injury, or environmental factors [9]. However, the renewal and di ﬀerentiation ability of NSC is limited; in the process of aging or pathological conditions, neuronal cell loss is much more than newly gen- erated neurons and glial cells from NSCs, resulting in di ﬀer- ent neurological disorders including Alzheimer ’s disease [10], Parkinson ’s disease [11], Huntington ’s disease [12], neuroendocrine tumors [13], and ataxia [14]. Therefore, the regulation on the renewal and di ﬀerentiation of NSCs or NSC transplantation therapy are considered an important Hindawi Stem Cells International Volume 2018, Article ID 6087143, 10 pages https://doi.org/10.1155/2018/6087143 therapeutic strategy for the treatment of these neurodegener- ative diseases.Among the regulatory mechanisms of the renewal and di ﬀerentiation of NSCs, epigenetic modi ﬁcation plays a crit- ical role in monitoring the phase transition during individual development, maintaining the directional di ﬀerentiation of stem cells, regulating the proliferation of speci ﬁc cells, and controlling the process of di ﬀerentiation [15, 16]. For exam- ple, in the process of umbilical cord mesenchymal stem cells (UMSCs) being di ﬀerentiated to neural stem-like cells (uNSCLs), E1A-like inhibitor of di ﬀerentiation 3 (EID3), an important member of EID gene family that has the main function of p300/CBP inhibitors (a transcriptional coactiva- tor) in response to cell transformation, growth arrest, or cell apoptosis, directly interacts with DNMT3A, a DNA methyl- transferase (DNMT) for DNA methylation, suggesting that DNA methylation may be involved the regulation of transdif- ferentiating from UMSCs to uNSCLs as a key mechanism in epigenetic regulation of stem cell reprogramming [17]. So far, epigenetic modiﬁ cation is a hot topic in recent years. Except for DNA methylation, histone modi ﬁcation, micro-RNA, chromatin remodeling, and other epigenetic modi ﬁcation are found to play important roles in the regulation of stem cells [18]. In this article, we will review the recent advances of di ﬀerent epigenetic modiﬁ cations on NSCs, but mainly focus on the role of 5hmC as a new player in the regulation of the renewal and di ﬀerentiation of ESCs or NSCs.

2. Recent Advances on Epigenetic Regulation on Stem Cells It is strongly believed that the basis of cell di ﬀerentiation in ontogeny is based on the regulation of intracellular factors, while environmental factors also play a role as a main cause [19]. Epigenetic modi ﬁcations including methylation, acety- lation, ubiquitination, and phosphorylation on DNA, RNA, or proteins mediate the interaction between the environment and the organism [20]. Interestingly, recent evidences dem- onstrate that epigenetic modiﬁ cation changes can be inher- ited to the next generation [21]. Here, we present a brief overview of current advances on epigenetic modi ﬁcations and NSCs.

2.1. DNA Methylation. The increasing evidences demonstrate that DNA methylation is involved in the proliferation and di ﬀerentiation of stem cells [22]. DNA methylation prevents transcriptional factors from binding to promoters, such as Oct4 and Nanog, thereby limiting gene expression [23].

The process of DNA methylation is catalyzed by DNA meth- yltransferase, mainly DNMT1, DNMT3A, and DNMT3B.

DNMT3 enzyme is a de novo methyltransferase [24] and DNMT1 is mainly involved in the maintaining of DNA methylation in dividing somatic cells [25]. The deletion of DNMT3A in hematopoietic stem cells impaired the di ﬀeren- tiation of transplanted hematopoietic stem cells and increased the level of hematopoietic stem cells in the bone marrow [22]. In skeletal muscle stem cells, the DNA methyl- ation of CpG dinucleotide in the promoter or enhancer region reduces gene expression of Pax7 and MyoD [26]. Similarly, Uhrf1 (ubiquitin-like PHD ring ﬁnger-1; also known as Np95) mainly interacts with DNMT1 to maintain DNA methylation in NSCs; the deletion of Uhrf1 in NSCs leads to increase the global DNA methylation and delayed neurodegeneration [27]. Recent evidences showed that Methyl CpG binding domain protein 1 (MBD1) is expressed in neural stem cells (aNSCs) of dentate gyrus of the adult hippocampus and maintains the integrity and stemness of NSC by inhibiting di ﬀerentiation [28]. MBD1 and Methyl CpG binding protein 2 (Mecp2) belong to the methyl-CpG- binding protein family and play a key role to link DNA meth- ylation and transcriptional regulation on di ﬀerentiation genes [29]. MBD1 de ﬁciency leads to the accumulation of undi ﬀerentiated NSCs and impaired transition into the neu- ronal lineage [28]. DNA methylation is closely related to stem cell-related diseases. A recent study found that there are a large number of gene mutations of DNMT3A in acute myeloid leukemia which is a malignant tumor characterized by clonal stem cell proliferation and aberrant block in di ﬀer- entiation [30]. Fetal alcohol syndrome showed that alcohol exposure to cultured NSCs altered normal DNA methylation programming of key neural stem cell genes and retarded NSC migration and di ﬀerentiation [31], supporting the role of aberrant patterns of DNA methylation in fetal neural devel- opment after embryonic alcohol exposure.

2.2. Histone Modi ﬁcation. Histone modiﬁ cation refers to the process of histone methylation, acetylation, phosphorylation, polyadenylation, ubiquitination, and ADP glycosylation under the action of related enzymes. Histone-mediated epi- genetic gene silencing is to remove acetyl groups from histone tails catalyzed by histone deacetylase (HDAC) enzymes and enhance the binding of histones to DNA and the aggregation of chromosomes, preventing transcription factors into the regulatory region [32]. HDAC1 is highly expressed in the oligodendrocyte di ﬀerentiation period of the corpus callosum; HDAC inhibitors blocked oligodendro- cyte di ﬀerentiation and cause demyelination in the corpus callosum of postnatal rats [33]. The recent study indicated that the Arf-p53 axis also might be involved in the regulation of histone acetylation on the proliferation and senescence of the neurospheres [34]. Histone demethylation is also an important histone mod- i ﬁ cation. It has two families, LSD1 (Lysine-speci ﬁc demethy- lase 1) and JmjC (a domain), to regulate the proliferation and di ﬀerentiation of stem cells. Inhibiting the activity of LSD1 or knockdown of LSD1 expression leads to the decreased prolif- eration of neural stem cells [35]. In addition, LSD1 plays a crucial role in maintaining the silencing of several develop- mental genes in human embryonic stem cells by regulating the balance between H3K4 (lysine 4 on histone H3 protein) and H3K27 methylation in its regulatory region [36]. Thus, histone modi ﬁcations play a role in inducing NSC di ﬀerenti- ation into neurons and glial lineages, but the mechanisms are still not clear.

2.3. Noncoding RNA. Noncoding RNAs (ncRNAs) are a class of RNA molecules that have no ability to translate into pro- teins but function as regulatory factors at transcriptional or 2 Stem Cells International posttranscriptional levels, including ribosomal RNAs (rRNAs), microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), long noncoding RNAs (lncRNAs), and others [37]. These ncRNAs have shown to play distinct but also con- served roles in regulation of diﬀerentiation of NSCs [38–40].

Among di ﬀerent ncRNAs, current evidences demonstrate that miRNAs play critical roles in the regulation of di ﬀeren- tiation of NSCs. miRNAs are a group of small RNA mole- cules of 20–24 nucleotides widely found in eukaryotes.

They bind to target mRNAs to regulate their gene expression by promoting the degradation of target mRNAs. Similarly, microRNA is also involved in the regulation of NSC di ﬀeren- tiation and proliferation dynamic homeostasis; for example, high levels of miR-184, which are inhibited by methyl-CpG binding protein 1, promote stem cell proliferation but inhibit adult neural stem/progenitor cell (aNSCs) di ﬀerentiation [41]. MiR-145 directly regulates Nurr1 (a nuclear receptor) expression level, and overexpression of miR-145 inhibits the di ﬀerentiation e ﬀect of BMP2; knockdown of miR-145 promoted the upregulation of Nurr1, resulting in the di ﬀer- entiation of NSCs into dopaminergic neurons [42]. Micro- RNA can regulate many factors such as CT4, SOX2, and KLF4 in embryonic stem cells that are the direct targets of miR-145. The deletion of miR-145 increases the expression of OCT4, SOX2, and KLF4 and further inhibits the di ﬀeren- tiation of NSC [43]. Recent studies showed that aging process begin when hypothalamic stem cells that coexpress Sox2 and Bmi1 are ablated accompanying with substantial loss of hypothalamic cells; the injection of exosomal miRNA in the cerebrospinal ﬂuid, greatly prevented the cell aging process [44]. Therefore, more and more evidences showed that ncRNAs like miRNA are involved in the regulation of di ﬀer- entiation of NSCs.

3. Ten-Eleven Translocation (Tet) Proteins- 5hmC Modification-Related Enzymes Tet family proteins are a group of α-ketoglutarate ( α-KG) and Fe2+ ‐dependent monooxygenase to catalyze the con- version of 5mC to 5hmC, concluding Tet1, Tet2, and Tet2 [45]. In 2009, Tahiliani et al. found that Tet1 catalyzes the reaction of 5mC to 5hmC [46]; thereafter, Tet2 and Tet3 have been found to have similar catalytic activity [47]. Although the main functions of the three enzymes are to oxidize 5mC to 5hmC, the distribution of the enzymes is di ﬀerent. The expression of Tet1 protein in embryonic stem cells and ner- vous system is high [48–50]; Tet2 is widely distributed and relatively high in hematopoietic system; Tet3 is mainly expressed in colon, muscle tissues, and less in brain tissues [51]. The three Tet enzymes contain a structurally similar carboxyl terminal catalytic region, which catalyzes the syn- thesis of 5hmC activity [45]. The catalytic domain of Tet proteins has 3 metal ion (Fe2+) and α-KG binding site to enhance its catalytic activity [46]. Tet1 and Tet3 have an amino terminal CXXC zinc ﬁnger protein domain, whereas Tet2 lacks this structure and needs to be assisted by IDAX protein with similar functions [52]. The CXXC domain protein of Tet2 is encoded by a distinct gene IDAX. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA, and interacts directly with the catalytic domain of Tet2 [52]. IDAX (also known as CXXC4), a reported inhibitor of Wnt signaling, regulates Tet2 protein expression [53]. Unexpectedly, IDAX expres- sion results in caspase activation and Tet2 protein downreg- ulation in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits Tet2 to DNA before degradation [52]. Notably, the IDAX- related protein CXXC5 resembles IDAX in inhibiting Wnt signaling [54]. Therefore, the distribution and structure of Tet enzymes determine the distribution of 5hmC modiﬁ ca- tions in brain and their di ﬀerent roles in di ﬀerent diseases.

Tet1 knockout mice showed impaired hippocampal neuro- genesis resulting in learning and memory de ﬁciency [55].

Tet2 functional disruption or knockout in ﬂuences hemato- poietic cell homeostasis and hematopoietic di ﬀerentiation and promotes the development of myeloid malignancies [56]. Although either Tet1 or tet2 knockout mice are viable and fertile, Tet3 knockout mice are perinatally lethal [51].

These demonstrate the di ﬀerent roles of Tet proteins in the di ﬀerent tissues and in the devolvement of di ﬀerent organs.

The functions of Tet proteins and its related phenotypes in rodent animals and diseases in human are summarized in Table 1. 5-Hydroxymethylcytosine (5hmC), the oxidative product of 5mC, was found in mammals with surprisingly high abun- dance in 2009 [46, 57]. Recent studies showed that 5mC is not the ﬁnal chemical steps for gene silencing; Tet protein- associated DNA demethylation can transform 5-methyl cytosine (5mC) into 5-hydroxymethycytosine (5hmC), 5- formylcytosine (5fC), and 5-carbosycytosine (5caC), but 5fC and 5caC is much less than 5-hydroxymethylcytosine [58, 59]. Interestingly, for individual tissues, the levels of 5hmC, 5fC, and 5caC were not signi ﬁcantly related; for example, although 5hmC is more abundant in mouse brains than in ESCs, the levels of 5fC and 5caC are less abundant [45]. 5fC and 5caC can be further removed by the base exci- sion repair (BER) pathway and thymine-DNA glycosylase [60]. This pattern suggests that the di ﬀerent steps of demeth- ylation cycle are di ﬀerent in di ﬀerent tissues [61]. In addi- tion, Tet protein overexpression or depletion can increase or decrease the content of 5hmC, 5fC, and 5caC in the genome [61]. The discovery of Tet proteins speeds the explo- ration of the functions of 5hmC [46, 57]. Because of its important functions, 5hmC in DNA has been considered as the sixth base. More evidences show that demethylation by 5hmC regulates the proliferation of NSCs and neurogenesis [27]. Therefore, we further discuss the regulation of 5hmC on NSCs and related neurological diseases. 4. Tet Proteins and DNA 5hmC Modifications Are Involved in the Regulation on the Proliferation and Differentiation of NSCs The direction of cell di ﬀerentiation is determined by the speci ﬁc expression of tissue-speci ﬁc genes, while DNA 5mC is involved in the regulation of gene expression and 3 Stem Cells International diﬀerentiation of cells in a speci ﬁc direction [62 –64]. Previ- ous studies have shown that about 1.4% of CpG islands undergo a signi ﬁcant remethylation process during the dif- ferentiation of embryonic stem cells into NSCs and NPCs [65]. The increasing line of evidences indicate that 5mC directly inhibits transcription factors to bind to DNA [23] or recruits MeCP2 and MBD to form a complex and further prevent gene transcriptions that relate to the di ﬀerentiation of NSCs [66]. Therefore, DNA methylation plays an impor- tant role in neural cell di ﬀerentiation. Apparently, as an important demethylation mechanism, DNA 5hmC modi ﬁca- tion and Tet enzymes can be involved in the regulations of NSCs in theory. Recently, 5hmC has been found in the mammalian genome and has been shown to be about 10 times more abundant in neurons than in some peripheral nervous tissues [67]. This suggests that 5hmC may be a stable epigenetic marker involved in cell speci ﬁc mechanisms to achieve its function in the brain. More and more evidences demon- strated that Tet enzymes and Tet-mediated 5hmC modi ﬁca- tions are involved in the proliferation and di ﬀerentiation of ESCs and NSCs [29, 58, 68, 69]. Hahn et al. found that the increase of 5hmC modiﬁ cation in gene bodies is associated with genes important for neuronal functions during neuronal di ﬀerentiation in mouse brain regions; however, gene activa- tion for neuronal di ﬀerentiation is not related to substantial DNA demethylation [69]. At the same time, overexpression of Tet2 and Tet3 also promotes the progression of neuronal di ﬀerentiation [69]. Similarly, in Sirt6-knockout ESCs, the expression of Oct4, Sox2, and Nanog (the downstream of Sirt6) is inhibited and the upregulation of Tet enzymes and the signi ﬁcant increase of DNA 5hmC are found, resulting in ESC skewed development towards neuroectoderm [68].

This suggests that Sirt6-regulated ESC di ﬀerentiation is in a Tet enzyme and 5hmC-dependent manner [68], supporting Hahn et al. ’s results. A recent study further demonstrates that 5hmC dynamics is correlated with the di ﬀerentiation of aNSCs; however, Tet2 primarily contributes to 5hmC acqui- sition during the di ﬀerentiation of aNSCs [58]. Therefore, these evidences support the critical role of 5hmC modi ﬁca- tions in the di ﬀerentiation of NSCs.

Tet proteins, as the important enzymes for the conver- sion of 5mC to 5hmC, also showed their functions on the proliferation/di ﬀerentiation of NSCs. Tet1 depletion impairs hippocampal neurogenesis accompanied with poor learning and memory in mice; at the same time, Tet1 deﬁ ciency results in reduced neural progenitor pool in adult subgranu- lar zone [55]. These results provided in vivo evidences that Table 1: Tet proteins and their functions.

Genes Distribution StructureFunctions of Tet enzymes Knockout phenotypes in rodents Related diseases in humans Tet1 Mainly in ESCs and nervous system [48]. Contains CXXC, Cys-rich, and DSBH domains (1) Abnormal hippocampal neurogenesis, with learning and memory fading [55].

(2) Antidepressive phenotypes [94] (3) Skews di ﬀerentiation towards extraembryonic lineages in the teratoma [99]. (1) Acute leukemia [100].

(2) Gastric cancer ([101, 102], Deng, [103]).

(3) Breast cancer [104].

Tet2 Widely distributed and high in hematopoietic system [48]. Contains Cys-rich and DSBH domains without CXXC domain (1) Hematopoietic cell homeostasis and hematopoietic di ﬀerentiation impairment, myeloid malignancies [56].

(2) Retinal neurons developmental failure in zebra ﬁsh [105]. (1) Polycythemia vera [106, 107].

(2) Primary myelo ﬁbrosis [107].

(3) Myelodysplastic syndrome [106].

(4) Myeloproliferative neoplasm [108].

(5) Melanoma [109].

Tet3 Mainly in colon and muscle tissues, less in brain tissue [51]. Contains CXXC, Cys-rich, and DSBH domains (1) Developmental failure [72] and embryonic sublethality [110].

(2) Impaired di ﬀerentiation and increased apoptosis [72].

(3) Fear extinction impairments in mice [111].

(4) Abnormal morphogenesis of retinal neurons in zebra ﬁsh [105].

(5) Abnormal neural di ﬀerentiation and skewed toward cardiac mesodermal fate in mouse ESC [112]. NA Tet1/2 DKO Embryonic stage death and little normal growth [113] NA Tet1/3 DKO (1) Dendritic arborization inhibition in mice [114] (2) Holoprosencephaly [115]. NA Tet1/2/3 TKO Developmental disorders [116] NA CXXC: Cys-X-X-Cys domain; DSBH: double-stranded beta helix; DKO: double knockout; ESCs: embryonic stem cells; TKO: triple knockout; NA: not available.

4 Stem Cells International Tet1 deﬁciency in the central nervous system decrease the proliferation of adult NSCs in the hippocampal dentate gyrus. Moran-Crusio et al. showed that the depletion of Tet2 stimulates aNSCs proliferation but impairs the di ﬀer- entiation of aNSCs [56]. Tet2 interacted with the neuronal transcription activator Foxo3a, a member of the helix-turn- helix-like family proteins [70], and coregulated key genes involved in aNSC di ﬀerentiation [58]. Moreover, Tet3 plays critical roles in neural progenitor cell maintenance [71] but is not required for NSC fate [72]. However, how Tet proteins interact with cofactors to regulate target genes responsible for the proliferation and di ﬀerentiation of NSCs remains unclear. The possible regulative mechanisms are proposed in Figure 1.

5. Abnormal 5hmC and Neurological Diseases The growing evidences demonstrate that 5hmC has high abundance in the brain and play a critical role to in the main- tenance of normal neurodevelopment and functions of cen- tral nervous system. Thus, accumulating evidences showed that abnormal 5hmC modi ﬁcations are involved the patho- physiology of di ﬀerent neurological diseases.

5.1. Alzheimer ’s Disease (AD). Alzheimer’s disease (AD) is one of the most common age-related neurodegenerative dis- orders in the central nervous system, characterized by pro- gressive cognitive decline and loss of neuronal cells [73].

The pathogenesis of AD has yet to be de ﬁned, but there are evidences to support its genetic abnormalities, such as the mutations in β-amyloid precursor gene and presenilin1/2.

Previous study has shown that AD is associated with DNA methylation [74]. It has been found that levels of 5mC and DNMT in neurons are reduced in patients with AD [74].

At the same time, 5hmC level was reported to decrease in the hippocampal tissue of patients with AD [75]. However, a study has shown that brain 5mC and 5hmC levels increased in patients with AD [76]. The reasons for this inconsistency need to be further investigated. In APP-presenilin1 double transgenic mice, 5hmC abundance in di ﬀerent brain regions showed di ﬀerential response to the pathogenesis [77].

Further gene ontology analyses indicated that di ﬀerential hydroxymethylation region- (DhMR-) associated genes are highly enriched in multiple signaling pathways involving neuronal development/di ﬀerentiation [77], suggesting that DNA 5hmC modi ﬁcation is an epigenetic modiﬁ er on neuro- genesis or NSC di ﬀerentiation in aging or AD [78]. Interest- ingly, Tet1 is found to decrease in the hippocampus of patients with AD [79]. Tet1 knockout mice show impaired hippocampal neurogenesis as well as learning and memory defects [55, 80]. Therefore, Tet1 functions as a critical enzyme to regulate 5hmC modi ﬁcations on those genes related to the proliferation and di ﬀerentiation of NSCs and further promotes neurogenesis in adult brains.

5.2. Huntington ’s Disease (HD). HD is an autosomal domi- nant disorder characterized by chorea, dystonia, slow and unexpected decline in cognitive function, and mental disor- ders [81]. At present, Huntington gene exon CAG repeats are considered as the major cause that leads to abnormal accumulation of the ﬁrst amino acid polyglutamine in hun- tingtin proteins. Despite extensive research, the pathogenesis of neurodegeneration in HD is still unknown. ADORA2A gene encodes an adenylate A2A receptor, a G protein- coupled receptor that is highly expressed in the normal basal ganglia and is severely reduced in HD [82]. Recent studies have shown that HD results in an increase of 5mC expression and a decrease of 5hmC expression at the 5 ′ -UTR end of the ADORA2A gene compared with the same age group [83].

Except for the decreased of ADORA2A gene 5hmC modiﬁ ca- tion, a signi ﬁcant decrease of global 5hmC modiﬁ cation is found in HD mice with 128 CAG repeats, indicating the involvement of 5hmC in the pathogenesis of HD and a novel epigenetic marker in HD [82]. Further 5hmC pro ﬁling anal- ysis indicates that most genes with di ﬀerentially hydroxy- methylated regions are highly related to the pathological changes in HD, suggesting that gene 5hmC modi ﬁcations are involved in the regulation of neurogenesis, neuronal function, and survival in HD brain [82]. Because previous studies have shown the abnormal neurogenesis in HD [84], aberrant epigenetic regulation on relevant genes may impair the neurogenesis in brains with HD. Recent study demon- strated that targeting histone modi ﬁcation to downregulate the key genes for the pathology of HD causes bene ﬁcial e ﬀ ects in a Drosophila model of HD [85]. Therefore, the modulation of 5hmC signature in HD may be an e ﬀective strategy to ameliorate the symptoms of HD.

5.3. Rett Syndrome. Rett syndrome is considered as an inher- ited disease characterized by progressive mental decline, autistic behavior, ataxia, and anxiety in the early life of those who suﬀ er from the disease. The etiology and genetic pattern of this disease remain unknown. The primary cause of Rett syndrome is caused by methyl CpG binding protein 2 (MeCP2) gene mutations that result in loss of function of MeCP2 [86]. Because brains have the highest expression of MeCP2, MeCP2 functional de ﬁciency causes neurological diseases such as Rett syndrome [87]. Recent study showed th at MeCP2 was identi ﬁed as the major 5hmc binding pro- tein in the brain to facilitate gene expression by organizing the chromatin [88]. Previous study showed a reverse correla- tion between MeCP2 and 5hmC level, suggesting that MeCP2 binds to 5mC blocking the conversion of 5mC to 5hmC [67]. MeCP2 mutations such as R133C (an MeCP2 residue mutated in Rett syndrome) preferentially abolish its binding ability to 5hmC and account for the role of 5hmC in the pathophysiology of Rett syndrome, supporting that 5hmC and MeCP2 constitute an epigenetic regulation com- plex to control cell di ﬀerentiation or chromatin structure [88]. Recent studies have shown that MeCP2 is required for brain development and neuronal di ﬀerentiation by inhibiting the ID1/Her2 (the zebra ﬁsh ortholog of mammalian Hes5) axis in zebra ﬁsh because genetic depletion of MeCP2 inhib- ited neuronal di ﬀerentiation but its overexpression promoted neuronal di ﬀerentiation [89]. However, it is still unclear whether the blocking of MeCP2 binding to 5hmC is respon- sible for neuronal di ﬀerentiation in Rett syndrome, as awaits more investigations. 5 Stem Cells International 5.4. Major Depressive Disorders (MDD).The high morbidity and suicide of depression has become a major health concern in the world [90]. However, the pathogenesis of MDD remains unclear. So far, genetic and environmental factors are considered to interact and participate in the MDD, in which environmental factors mainly a ﬀect gene transcription and expression through epigenetic modi ﬁcation. DNA meth- ylation is considered a major epigenetic modi ﬁcation from environmental stress [91]. 5hmC functions as a new DNA demethylation mechanism, however, its role in depressive disorders is unclear. Epigenetic 5hmC modi ﬁcation, to some extent, provides a possible mechanism for explaining envi- ronmental factors that a ﬀect gene expression. Recent reports showed that patients with MDD had decreased gray matter volume and white matter integrity in the hippocampus [92]. In addition, Bansal et al. found structural changes in the cerebral cortex of patients with MDD, indicating that thickening of the cerebral cortex is a compensatory nerve growth response [93]. Recent studies have also provided evi- dence that Tet1 knockout showed antidepressive phenotypes by a ﬀecting neurogenesis in the hippocampus [94]. There- fore, Tet proteins-mediated 5hmC modi ﬁcations on depression-related genes are involved the regulation of neu- rogenesis in the mechanisms of MDD. 6. Conclusions Epigenetic modi ﬁcation is likely to be the collective response to changes in environmental factors as a means of cells or organisms to mitigate the adverse e ﬀects [95]. The dynamic changes of methylation (5mC) and demethylation (5hmC) in DNA could a ﬀect its structure as well as the functions of genes and further lead to di ﬀerent kinds of diseases. Recent advances on 5hmC modi ﬁcation have demonstrated that Tet proteins and Tet-mediated 5hmC play important roles in the proliferation and di ﬀerentiation of NSCs. However, it is unclear how Tet protein, Tet-interacting factors, and DNA 5hmC in target genes interplay and regulate the devol- vement of NSCs. These need more investigations in the future. Recently, DNA N6-Methyldeoxyadenosine (6 mA) is Fe2+ Fe2+ Fe2+ Tets Tets Tets TFs TFs TFs Motif Nucleus Promoter/TSS of genes Promoter/TSS of genes 5hmC binding proteins Environmental stimuli Proliferation and di erentiation of NSC Promote gene transcription -KG -KG -KG 5mC 5hmC Figure 1: Tet proteins and 5-hmC mediated regulation of NSC proliferation and di ﬀerentiation. Under the conditions of environmental stimuli, some transcriptional factors (TFs) such as FOXO3a enhance the a ﬃnity to Tet proteins along with cofactors of Tet enzymes including α-KG and Fe 2+to form a functional complex. By binding to DNA motifs of the targeting genes, the TFs guide the Tet enzymes to catalyze the conversion of 5mC to 5hmC. Generation of 5hmC facilitates the recruitment of the 5hmC binding proteins or other factors to enhance the transcription of targeting genes, thereby regulating the proliferation and di ﬀerentiation of NSCs. 6 Stem Cells International emerging as a new DNA modiﬁcation and plays an important role in the regulation of the proliferation and di ﬀerentiation of NSCs [96–98]. The interaction or crosstalking of DNA 5hmC modiﬁ cation and 6 mA modiﬁ cation will be an inter- esting topic. Considering the critical role of neuronal stem cells in the neurological diseases, targeting epigenetic regula- tion, especially on DNA 5hmC modi ﬁcation, is a promising strategy for the treatment of these neurological diseases.

Disclosure Hang Zhou and Bin Wang are co-ﬁ rst authors.

Conflicts of Interest The authors declare that they have no conﬂ icts of interest.

Acknowledgments This study was supported by the grants from National Key R&D Program of China (2017YFE0103700), Natural Science Foundation of Jiangsu Province (BK20141281), Special Foundation Project on the Prospective Study of Social Development in Jiangsu Province (BE2013911), Jiangsu Six Categories of Talent Summit Fund (WSW-133), Social Development of Science and Technology Research Project in Yangzhou (YZ2011082), and Jiangsu Province 333 talent Project (BRA2016159).

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