Transposable Elements: A Common Feature of Neurodevelopmental and Neurodegenerative Disorders
2020; Elsevier BV; Volume: 36; Issue: 8 Linguagem: Inglês
10.1016/j.tig.2020.05.004
ISSN1362-4555
AutoresMarie E. Jönsson, Raquel Garza, Pia A. Johansson, Johan Jakobsson,
Tópico(s)Genomic variations and chromosomal abnormalities
ResumoTransposable elements (TEs) make up almost half of our genome but are mostly silenced via different epigenetic mechanisms such as histone modifications and DNA methylation.The loss of effective silencing of TEs can lead to their activation, which in turn can lead to mutagenic and gene regulatory consequences, as well as induction of the interferon defense pathway.The field of TE research has so far been hampered by technological limitations with recent advances in sequencing techniques greatly increasing our understanding of TE activation in various disease mechanisms.Aberrant TE activation has been reported in both neurodevelopmental and neurodegenerative disorders, making it an interesting common denominator, which opens up possibilities for alternative diagnostic and treatment strategies. The etiology of most neurological disorders is poorly understood and current treatments are largely ineffective. New ideas and concepts are therefore vitally important for future research in this area. This review explores the concept that dysregulation of transposable elements (TEs) contributes to the appearance and pathology of neurodevelopmental and neurodegenerative disorders. Despite TEs making up at least half of the human genome, they are vastly understudied in relation to brain disorders. However, recent advances in sequencing technologies and gene editing approaches are now starting to unravel the pathological role of TEs. Aberrant activation of TEs has been found in many neurological disorders; the resulting pathogenic effects, which include alterations of gene expression, neuroinflammation, and direct neurotoxicity, are starting to be resolved. An increased understanding of the relationship between TEs and pathological processes in the brain improves the potential for novel diagnostics and interventions for brain disorders. The etiology of most neurological disorders is poorly understood and current treatments are largely ineffective. New ideas and concepts are therefore vitally important for future research in this area. This review explores the concept that dysregulation of transposable elements (TEs) contributes to the appearance and pathology of neurodevelopmental and neurodegenerative disorders. Despite TEs making up at least half of the human genome, they are vastly understudied in relation to brain disorders. However, recent advances in sequencing technologies and gene editing approaches are now starting to unravel the pathological role of TEs. Aberrant activation of TEs has been found in many neurological disorders; the resulting pathogenic effects, which include alterations of gene expression, neuroinflammation, and direct neurotoxicity, are starting to be resolved. An increased understanding of the relationship between TEs and pathological processes in the brain improves the potential for novel diagnostics and interventions for brain disorders. Disorders affecting the central nervous system (CNS), such as psychiatric and neurodegenerative disorders, are now the leading cause of the global disease burden [1.GBD Neurology Collaborators (2019) Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2016; 18: 459-480Google Scholar]. The societal impact of these disorders is likely to substantially increase in the near future as the aging population continues to expand [2.Hou Y. et al.Ageing as a risk factor for neurodegenerative disease.Nat. Rev. Neurol. 2019; 15: 565-581Crossref PubMed Scopus (315) Google Scholar]. While the etiology and disease mechanism differ between various brain disorders, in most cases the cause of the disorder remains poorly understood and there are currently no effective treatments. Thus, new perspectives for disease understanding and therapeutic intervention are urgently needed. Here we propose that aberrant activation of TEs, resulting from epigenetic dysregulation during development and aging, contributes to the pathophysiology of human brain disorders. TEs are mobile genetic elements that have colonized the genome throughout evolution and make up at least 50% of the human genome [3.Jern P. Coffin J.M. Effects of retroviruses on host genome function.Annu. Rev. Genet. 2008; 42: 709-732Crossref PubMed Scopus (307) Google Scholar,4.Lander E.S. et al.Initial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (16367) Google Scholar]. TEs are classified into retrotransposons (see Glossary) (class I) and DNA transposons (class II) [5.Jurka J. et al.Repbase Update, a database of eukaryotic repetitive elements.Cytogenet. Genome Res. 2005; 110: 462-467Crossref PubMed Scopus (1973) Google Scholar] (Figure 1, Key Figure). While DNA transposons are active in bacteria, archaea, and many eukaryotes, they have become inactive in most mammals, including humans [6.Huang C.R. et al.Active transposition in genomes.Annu. Rev. Genet. 2012; 46: 651-675Crossref PubMed Scopus (210) Google Scholar]. In this review, we will focus on retrotransposons, so-called due to their transposition via a retrotranscribed RNA intermediary. Retrotransposons are subdivided into long-terminal repeat (LTR) elements and non-LTR elements. LTR elements contribute to around 8% of the human genome, but all appear to have lost their ability to retrotranspose. The non-LTRs are the most common TEs in the human genome, where one subtype in particular, the long interspersed nuclear elements (LINEs), make up nearly 20% of the genome. We carry more than 500 000 individual LINE-1 element copies in our genome, with the majority being ancient degenerated copies unable to retrotranspose [4.Lander E.S. et al.Initial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (16367) Google Scholar,7.Beck C.R. et al.LINE-1 elements in structural variation and disease.Annu. Rev. Genomics Hum. Genet. 2011; 12: 187-215Crossref PubMed Scopus (320) Google Scholar]. However, 80–100 LINE-1 elements in the human genome can still be active [8.Brouha B. et al.Hot L1s account for the bulk of retrotransposition in the human population.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 5280-5285Crossref PubMed Scopus (659) Google Scholar, 9.Philippe C. et al.Activation of individual L1 retrotransposon instances is restricted to cell-type dependent permissive loci.eLife. 2016; 5e13926Crossref PubMed Scopus (72) Google Scholar, 10.Tubio J.M.C. et al.Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.Science. 2014; 3451251343Crossref PubMed Scopus (208) Google Scholar] and provide nonautonomous support for the other classes of TEs that are also currently active in humans, the Alu and Sine-VNTR-Alu (SVA) elements. This ability to randomly insert new copies of themselves into the genome poses an obvious mutagenic threat: insertion into promoters or exons will likely lead to disruption of gene expression or function [11.Payer L.M. Burns K.H. Transposable elements in human genetic disease.Nat. Rev. Genet. 2019; 20: 760-772Crossref PubMed Scopus (49) Google Scholar]. In this review we will discuss the cellular machinery that normally represses TEs in the human brain, with a focus on DNA and histone methylation. We will discuss the evidence that indicates that these pathways are dysregulated in neurological disorders and the potential pathological consequences of TE activation, highlighting current clinical evidence. We will discuss TE activation as a possible common pathological mechanism between seemingly unrelated neurological disorders. Finally, we will assess the particular challenges of TE analysis and how recent methodological development has greatly improved TE-related research and will continue to do so. It is becoming increasingly clear that TEs may play a role in human disease. As mentioned earlier, a few TEs in the human genome can still retrotranspose (i.e., move and amplify through a copy-and-paste mechanism). It is currently estimated that more than one in every 20 births results in a new germline transposition event, with Alu insertions being the most common (one in 20 births), followed by LINE-1 and SVA insertions (one in every 100–200 births) [12.Ewing A.D. Kazazian Jr., H.H. High-throughput sequencing reveals extensive variation in human-specific L1 content in individual human genomes.Genome Res. 2010; 20: 1262-1270Crossref PubMed Scopus (218) Google Scholar, 13.Huang C.R. et al.Mobile interspersed repeats are major structural variants in the human genome.Cell. 2010; 141: 1171-1182Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 14.Xing J. et al.Mobile elements create structural variation: analysis of a complete human genome.Genome Res. 2009; 19: 1516-1526Crossref PubMed Scopus (208) Google Scholar]. This activity has resulted in a large degree of TE polymorphism within the human population (Box 1) and these polymorphic alleles may, in some instances, cause detrimental effects [11.Payer L.M. Burns K.H. Transposable elements in human genetic disease.Nat. Rev. Genet. 2019; 20: 760-772Crossref PubMed Scopus (49) Google Scholar]. Furthermore, somatic transposition events can be mutagenic and result in pathological consequences, in particular those occurring during early development [15.Bedrosian T.A. et al.Early life experience drives structural variation of neural genomes in mice.Science. 2018; 359: 1395-1399Crossref PubMed Scopus (65) Google Scholar, 16.Erwin J.A. et al.L1-associated genomic regions are deleted in somatic cells of the healthy human brain.Nat. Neurosci. 2016; 19: 1583-1591Crossref PubMed Google Scholar, 17.Evrony G.D. et al.Cell lineage analysis in human brain using endogenous retroelements.Neuron. 2015; 85: 49-59Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar, 18.Muotri A.R. et al.Somatic mosaicism in neuronal precursor cells mediated by L1 retrotransposition.Nature. 2005; 435: 903-910Crossref PubMed Scopus (632) Google Scholar, 19.Upton K.R. et al.Ubiquitous L1 mosaicism in hippocampal neurons.Cell. 2015; 161: 228-239Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar].Box 1Transposable Elements (TEs) Have the Potential to Influence Human Diversity through the Presence of Polymorphic AllelesA polymorphic TE (polyTE) is a newly integrated TE that is not fixed in the human population. Polymorphism can occur both in germline and somatic cells. When the retrotransposition event occurs in the germline, the polyTE is passed on to the next generation. If the new insertion is harmless or beneficial for the host genome, it might increase its frequency in the population over time and perhaps become fixed.In contrast, if the event happens in a somatic cell it creates mosaicism and the effect is limited to the individual and not inherited. These types of insertions have been reported in several different types of tumors and might therefore play a role in the pathology of these diseases. However, mosaicism is also found in normal postmortem brain tissue and might therefore contribute to the functional diversity of a cell population.The number of polyTEs present in the human population has been difficult to estimate, since reference genomes are not representative. However, newly developed long-read sequencing techniques (Pacific Biosciences, PacBio) have made reference-free genome assemblies much more accurate, increasing the sensitivity to subtle variations among the population. As a result, recent studies have estimated that there are more than 400 million polyTEs present in the human population and that any two human haploid genomes differ by around a thousand polyTEs [103.Bourque G. et al.Ten things you should know about transposable elements.Genome Biol. 2018; 19: 199Crossref PubMed Scopus (188) Google Scholar,104.Richardson S.R. et al.L1 retrotransposons and somatic mosaicism in the brain.Annu. Rev. Genet. 2014; 48: 1-27Crossref PubMed Google Scholar]. A polymorphic TE (polyTE) is a newly integrated TE that is not fixed in the human population. Polymorphism can occur both in germline and somatic cells. When the retrotransposition event occurs in the germline, the polyTE is passed on to the next generation. If the new insertion is harmless or beneficial for the host genome, it might increase its frequency in the population over time and perhaps become fixed. In contrast, if the event happens in a somatic cell it creates mosaicism and the effect is limited to the individual and not inherited. These types of insertions have been reported in several different types of tumors and might therefore play a role in the pathology of these diseases. However, mosaicism is also found in normal postmortem brain tissue and might therefore contribute to the functional diversity of a cell population. The number of polyTEs present in the human population has been difficult to estimate, since reference genomes are not representative. However, newly developed long-read sequencing techniques (Pacific Biosciences, PacBio) have made reference-free genome assemblies much more accurate, increasing the sensitivity to subtle variations among the population. As a result, recent studies have estimated that there are more than 400 million polyTEs present in the human population and that any two human haploid genomes differ by around a thousand polyTEs [103.Bourque G. et al.Ten things you should know about transposable elements.Genome Biol. 2018; 19: 199Crossref PubMed Scopus (188) Google Scholar,104.Richardson S.R. et al.L1 retrotransposons and somatic mosaicism in the brain.Annu. Rev. Genet. 2014; 48: 1-27Crossref PubMed Google Scholar]. In addition to the potential mutagenic insertion into the genome upon retrotransposition, the actual transcription of TEs (TE transcription) may have negative consequences. The TE-derived cytosolic nucleic acids can cause activation of the innate immune response [20.Roulois D. et al.DNA-demethylating agents target colorectal cancer cells by inducing viral mimicry by endogenous transcripts.Cell. 2015; 162: 961-973Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar] (Box 2) as well as serving as a source of regulatory noncoding RNAs [21.Lu X. et al.The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity.Nat. Struct. Mol. Biol. 2014; 21: 423-425Crossref PubMed Scopus (210) Google Scholar, 22.Spengler R.M. et al.Functional microRNAs and target sites are created by lineage-specific transposition.Hum. Mol. Genet. 2014; 23: 1783-1793Crossref PubMed Scopus (42) Google Scholar, 23.Petri R. et al.LINE-2 transposable elements are a source of functional human microRNAs and target sites.PLoS Genet. 2019; 15e1008036Crossref PubMed Scopus (5) Google Scholar]. The TE transcripts can also be translated into TE-derived peptides, which have been shown to be cytotoxic [24.Li W. et al.Human endogenous retrovirus-K contributes to motor neuron disease.Sci. Transl. Med. 2015; 7307ra153Crossref PubMed Scopus (191) Google Scholar].Box 2Transposable Elements (TEs) Have the Potential to Activate an Innate Immune ResponseThe innate immune system is an ancient part of our immune system and acts as a nonspecific first line of defense against different pathogens, such as viruses and bacteria. Pattern recognition receptors (PRRs) detect the infectious agent and trigger signaling cascades that lead to the nuclear activation of immune genes encoding proinflammatory effectors, such as cytokines and interferons (IFNs). The activation of the innate immune system is critical for the more specific adaptive immune responses. One of the most studied PRRs are Toll-like receptors (TLRs). They were initially identified on sentinel cells but have recently also been discovered to be expressed in neural cells.Although TEs have become domesticated, they still retain virus-like structures (see Figure 1A in the main text) and might appear pathogenic to the host upon activation, thus triggering an innate immune response. Thus, the loss of epigenetic repression leads to transcriptional activation, when TE-derived transcripts are transported into the cytoplasm (Figure I,1), where the single stranded RNA (ssRNA) can be used as a template for cDNA in the presence of reverse transcriptase, generating RNA:DNA hybrids (Figure I,2). TLRs located in the endosomal membrane can sense these different retroviral nucleic acids. These TLRs are subsequently incorporated into an autophagosome and merged with an endosome where they are detected (Figure I,3), resulting in an activation of the innate immune system.Alternatively, the single stranded DNA (ssDNA) generated from the reverse transcription can be used to make double stranded DNA (dsDNA) (Figure I,4) before being transported into the nucleus for reintegration into the genome (Figure I,5) (thereby completing a retrotransposition event). As a consequence, ssDNA molecules could accumulate in the cytoplasm and be detected by the cytoplasmic PRRs (Figure I,6,7), thereby triggering an IFN response.Additionally, the TE-derived transcripts exported from the nuclei may function as mRNAs and be translated into peptides/proteins (Figure I,8). If the TE-derived proteins are released or presented on the cell membrane, the TLRs located in the cell membrane can recognize TE-derived proteins as foreign, triggering the innate immune system (Figure I,9).The different modes of detection of the TE-derived molecules by different types of PRRs trigger signaling cascades that lead to the nuclear activation of immune genes encoding for proinflammatory effectors, such as cytokines and IFN. Producing IFN upon immune activation can establish a positive feedback loop that further upregulates IFN-stimulated genes, increasing the immune reaction. Thus, TEs hold the potential to activate the immune system in multiple ways and offer a potential trigger for the neuroinflammation found in neurodevelopmental and neurodegenerative disorders. For further reading on this topic see, for example, [113.Ishak C.A. et al.Deregulation of retroelements as an emerging therapeutic opportunity in cancer.Trends Cancer. 2018; 4: 583-597Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 114.Saleh A. et al.Transposable elements, inflammation, and neurological disease.Front. Neurol. 2019; 10: 894Crossref PubMed Scopus (8) Google Scholar, 115.Hurst T.P. Magiorkinis G. Activation of the innate immune response by endogenous retroviruses.J. Gen. Virol. 2015; 96: 1207-1218Crossref PubMed Scopus (25) Google Scholar, 116.Kumar V. Toll-like receptors in the pathogenesis of neuroinflammation.J. Neuroimmunol. 2019; 332: 16-30Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. The innate immune system is an ancient part of our immune system and acts as a nonspecific first line of defense against different pathogens, such as viruses and bacteria. Pattern recognition receptors (PRRs) detect the infectious agent and trigger signaling cascades that lead to the nuclear activation of immune genes encoding proinflammatory effectors, such as cytokines and interferons (IFNs). The activation of the innate immune system is critical for the more specific adaptive immune responses. One of the most studied PRRs are Toll-like receptors (TLRs). They were initially identified on sentinel cells but have recently also been discovered to be expressed in neural cells. Although TEs have become domesticated, they still retain virus-like structures (see Figure 1A in the main text) and might appear pathogenic to the host upon activation, thus triggering an innate immune response. Thus, the loss of epigenetic repression leads to transcriptional activation, when TE-derived transcripts are transported into the cytoplasm (Figure I,1), where the single stranded RNA (ssRNA) can be used as a template for cDNA in the presence of reverse transcriptase, generating RNA:DNA hybrids (Figure I,2). TLRs located in the endosomal membrane can sense these different retroviral nucleic acids. These TLRs are subsequently incorporated into an autophagosome and merged with an endosome where they are detected (Figure I,3), resulting in an activation of the innate immune system. Alternatively, the single stranded DNA (ssDNA) generated from the reverse transcription can be used to make double stranded DNA (dsDNA) (Figure I,4) before being transported into the nucleus for reintegration into the genome (Figure I,5) (thereby completing a retrotransposition event). As a consequence, ssDNA molecules could accumulate in the cytoplasm and be detected by the cytoplasmic PRRs (Figure I,6,7), thereby triggering an IFN response. Additionally, the TE-derived transcripts exported from the nuclei may function as mRNAs and be translated into peptides/proteins (Figure I,8). If the TE-derived proteins are released or presented on the cell membrane, the TLRs located in the cell membrane can recognize TE-derived proteins as foreign, triggering the innate immune system (Figure I,9). The different modes of detection of the TE-derived molecules by different types of PRRs trigger signaling cascades that lead to the nuclear activation of immune genes encoding for proinflammatory effectors, such as cytokines and IFN. Producing IFN upon immune activation can establish a positive feedback loop that further upregulates IFN-stimulated genes, increasing the immune reaction. Thus, TEs hold the potential to activate the immune system in multiple ways and offer a potential trigger for the neuroinflammation found in neurodevelopmental and neurodegenerative disorders. For further reading on this topic see, for example, [113.Ishak C.A. et al.Deregulation of retroelements as an emerging therapeutic opportunity in cancer.Trends Cancer. 2018; 4: 583-597Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar, 114.Saleh A. et al.Transposable elements, inflammation, and neurological disease.Front. Neurol. 2019; 10: 894Crossref PubMed Scopus (8) Google Scholar, 115.Hurst T.P. Magiorkinis G. Activation of the innate immune response by endogenous retroviruses.J. Gen. Virol. 2015; 96: 1207-1218Crossref PubMed Scopus (25) Google Scholar, 116.Kumar V. Toll-like receptors in the pathogenesis of neuroinflammation.J. Neuroimmunol. 2019; 332: 16-30Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar]. Finally, TEs are now also considered to be important gene regulatory elements. They can be binding sites for gene regulatory factors, thus acting as an alternative promoter, enhancer, or other regulatory elements (reviewed in [25.Chuong E.B. et al.Regulatory activities of transposable elements: from conflicts to benefits.Nat. Rev. Genet. 2017; 18: 71-86Crossref PubMed Scopus (450) Google Scholar,26.Friedli M. Trono D. The developmental control of transposable elements and the evolution of higher species.Annu. Rev. Cell Dev. Biol. 2015; 31: 429-451Crossref PubMed Scopus (122) Google Scholar]). While dysregulation of such networks has the potential to contribute to pathological mechanisms, there is also evidence suggesting that this regulatory aspect of TEs might lead to beneficial effects, in particular during development (Box 3).Box 3Transposable Elements (TEs): Foes and Friends?TEs can impact on the human genome in various ways. On one hand, TEs pose a threat to genomic integrity as their activation may result in transposition events that, upon integration in the genome, might result in deleterious mutations. The host has therefore evolved numerous mechanisms to prevent transposition. For example, TEs are usually covered with DNA/histone methylation marks that silence expression.On the other hand, TEs have the potential to be co-opted and provide benefit for the host in a number of ways. For example, silenced TEs can create repressive hubs that can negatively affect the expression of nearby genes. In cases where TEs escape repression, they can be transcribed as noncoding RNA or act as cis- or trans-regulatory elements, such as enhancers or promoters.In the 1950s it was already recognized that TEs are genetic elements that have the potential to alter the genetic landscape and influence gene expression when they integrate into new sites in their host genome [117.McClintock B. The origin and behavior of mutable loci in maize.Proc. Natl. Acad. Sci. U. S. A. 1950; 36: 344-355Crossref PubMed Google Scholar]. Today, it is becoming increasingly clear that TEs act as important gene regulatory elements and serve as a rich source for genome innovation. For further reading on this topic see, for example, [25.Chuong E.B. et al.Regulatory activities of transposable elements: from conflicts to benefits.Nat. Rev. Genet. 2017; 18: 71-86Crossref PubMed Scopus (450) Google Scholar,26.Friedli M. Trono D. The developmental control of transposable elements and the evolution of higher species.Annu. Rev. Cell Dev. Biol. 2015; 31: 429-451Crossref PubMed Scopus (122) Google Scholar]. TEs can impact on the human genome in various ways. On one hand, TEs pose a threat to genomic integrity as their activation may result in transposition events that, upon integration in the genome, might result in deleterious mutations. The host has therefore evolved numerous mechanisms to prevent transposition. For example, TEs are usually covered with DNA/histone methylation marks that silence expression. On the other hand, TEs have the potential to be co-opted and provide benefit for the host in a number of ways. For example, silenced TEs can create repressive hubs that can negatively affect the expression of nearby genes. In cases where TEs escape repression, they can be transcribed as noncoding RNA or act as cis- or trans-regulatory elements, such as enhancers or promoters. In the 1950s it was already recognized that TEs are genetic elements that have the potential to alter the genetic landscape and influence gene expression when they integrate into new sites in their host genome [117.McClintock B. The origin and behavior of mutable loci in maize.Proc. Natl. Acad. Sci. U. S. A. 1950; 36: 344-355Crossref PubMed Google Scholar]. Today, it is becoming increasingly clear that TEs act as important gene regulatory elements and serve as a rich source for genome innovation. For further reading on this topic see, for example, [25.Chuong E.B. et al.Regulatory activities of transposable elements: from conflicts to benefits.Nat. Rev. Genet. 2017; 18: 71-86Crossref PubMed Scopus (450) Google Scholar,26.Friedli M. Trono D. The developmental control of transposable elements and the evolution of higher species.Annu. Rev. Cell Dev. Biol. 2015; 31: 429-451Crossref PubMed Scopus (122) Google Scholar]. Given the potential pathological consequences of aberrant TE activation, it is not surprising that the majority of TEs are transcriptionally silenced in adult tissues. It has been known for decades that this silencing correlates with the presence of DNA methylation, a covalent modification that occurs on cytosines [27.Yoder J.A. et al.Cytosine methylation and the ecology of intragenomic parasites.Trends Genet. 1997; 13: 335-340Abstract Full Text PDF PubMed Scopus (1449) Google Scholar]. In most cases, DNA methylation is found on CG dinucleotides, often referred to as CpGs. The establishment of this DNA modification is mediated through a family of enzymes called DNA methyltransferases (DNMTs). In humans there are three DNMTs: DNMT1, DNMT3A, and DNMT3B [28.Li E. et al.Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Cell. 1992; 69: 915-926Abstract Full Text PDF PubMed Scopus (3066) Google Scholar, 29.Okano M. et al.DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development.Cell. 1999; 99: 247-257Abstract Full Text Full Text PDF PubMed Scopus (4102) Google Scholar, 30.Okano M. et al.Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases.Nat. Genet. 1998; 19: 219-220Crossref PubMed Scopus (1201) Google Scholar]. DNMT3A and 3B are mainly de novo methyltransferases that are responsible for establishing DNA methylation patterns, which occur mainly during embryogenesis, while DNMT1 is a maintenance methyltransferase that replicates DNA methylation patterns during cell division (Figure 2A ). Intriguingly, DNMT1 is also highly expressed in adult postmitotic neurons, indicating additional roles for this enzyme in the brain [31.Feng J. et al.Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.Nat. Neurosci. 2010; 13: 423-430Crossref PubMed Scopus (700) Google Scholar]. CpG-DNA methylation of promoter regions correlates with transcriptional repression. However, it is not completely known how the presence of DNA methylation results in transcriptional silencing: it is thought that this occurs through several different mechanisms [32.Greenberg M.V.C. Bourc'his D. The diverse roles of DNA methylation in mammalian development and disease.Nat. Rev. Mol. Cell Biol. 2019; 20: 590-607Crossref PubMed Scopus (337) Google Scholar]. For example, DNA methylation can attract protein complexes that mediate the formation of heterochromatin. 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