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Review

Histone Lysine Methylation and Neurodevelopmental Disorders

by
Jeong-Hoon Kim
1,2,†,
Jang Ho Lee
3,†,
Im-Soon Lee
3,
Sung Bae Lee
4,* and
Kyoung Sang Cho
3,*
1
Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
2
Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Korea
3
Department of Biological Sciences, Konkuk University, Seoul 05029, Korea
4
Department of Brain & Cognitive Sciences, DGIST, Daegu 42988, Korea
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2017, 18(7), 1404; https://doi.org/10.3390/ijms18071404
Submission received: 13 June 2017 / Revised: 25 June 2017 / Accepted: 27 June 2017 / Published: 30 June 2017
(This article belongs to the Special Issue Epigenetics of Neurodevelopmental Disorders)
Browse Figure
Versions Notes

Abstract

:
Methylation of several lysine residues of histones is a crucial mechanism for relatively long-term regulation of genomic activity. Recent molecular biological studies have demonstrated that the function of histone methylation is more diverse and complex than previously thought. Moreover, studies using newly available genomics techniques, such as exome sequencing, have identified an increasing number of histone lysine methylation-related genes as intellectual disability-associated genes, which highlights the importance of accurate control of histone methylation during neurogenesis. However, given the functional diversity and complexity of histone methylation within the cell, the study of the molecular basis of histone methylation-related neurodevelopmental disorders is currently still in its infancy. Here, we review the latest studies that revealed the pathological implications of alterations in histone methylation status in the context of various neurodevelopmental disorders and propose possible therapeutic application of epigenetic compounds regulating histone methylation status for the treatment of these diseases.

1. Introduction

Post-translational modifications of histone proteins in eukaryotic cells serve as crucial regulatory mechanisms of gene expression and are important for maintaining genomic integrity [1,2]. The histone modifications, such as its acetylation, methylation, phosphorylation, and ubiquitination, influence genomic activity by altering the binding force of DNA to histones or by acting as marks that recruit specific histone binding proteins [2]. Among these histone modifications, methylation has been implicated in heterochromatin formation and the regulation of promoter activity [3,4]. The histone residues, on which methylation occurs, include the following lysine and arginine residues: H3 (K4, 9, 27, 36, and 79), H4K20, H3 (R2, 8, 17, and 26), and H4R3 [5,6] (Figure 1a). These methylation sites are evolutionarily well conserved [7]. A variety of histone methyltransferases (writers), histone demethylases (erasers), and methylated histone binding proteins (readers) have been identified in various eukaryotic genomes [8]. Their site-specific molecular functions have been defined by biochemical and genetic studies [2,8] (Table 1).
Dysregulation of epigenetic modifications are associated with various human diseases, including neurodevelopmental disorders [9,10]. In particular, an increasing number of mutations in histone lysine methylation-related genes have been identified as intellectual disability-associated genes by exome sequencing with patients’ samples [11,12,13,14] (Figure 1b and Table 2). This highlights the importance of proper control of histone methylation during neurogenesis. In the current article, we provide an overview of the latest updates on the pathological implication of alterations in histone lysine methylation status in terms of neurodevelopmental disorders. Through this, we try to predict the future direction of research on this emerging field.

2. Histone Lysine Methylations and Related Factors

In most cases, methylation of histone H3 lysine 4 (H3K4me) is primarily found at enhancers and promoters of actively transcribed genes, and the methylation status of genes (i.e., mono-, di-, tri-methylation) correlates with its transcriptional activity [15,16]. Members of the lysine methyl transferase 2 (KMT2) family catalyze the addition of methyl groups to H3K4 at the post-translational level, while lysine demethylases (KDMs) remove the methyl groups. This dynamically modulates chromatin structures [17,18]. The KMT2 family, which is highly conserved throughout eukaryotes, can be evolutionarily divided into three subgroups (i.e., KMT2A and KMT2B, KMT2C and KMT2D, and SETD1A and SETD1B) [4,19]. In addition, SMYD2 and SETD3 also have been identified as H3K4 methyltransferases, and eight KDMs are reported to target the H3K4me [4,20].
Methylation of histone H3 lysine 9 (H3K9me) is associated with both heterochromatin formation and gene silencing in euchromatin [2]. H3K9me acts as a binding sit Counseling, e for HP1 [21,22] which forms a complex with chromatin-modifying factors crucial for heterochromatin formation when recruited to H3K9me [23,24]. In the euchromatic region, H3K9me contributes to HP1-mediated gene silencing [25]. H3K9me is catalyzed by several methyltransferases, such as EHMT1, EHMT2, SUV39H1, SUV39H2, SETDB1, dimeric EHMT1-EHMT2, and the PRDM family, and erased by the following lysine demethylases: KDM1, KDM3, KDM4, PHF2, and PHF8 [8,26,27].
Histone H3 lysine 27 methylation (H3K27me) is a repressive chromatin mark that is involved in gene silencing during development and X-chromosome inactivation [28,29]. H3K27me is associated with the repression of developmental regulator genes in human and murine embryonic stem cells (ESCs) [30,31]. Intriguingly, a variety of promoters characteristically contain both H3K4me3 (an activating mark) and H3K27me (a repressive mark) in pluripotent ESCs, which is referred to as “bivalency.” The change in the bivalent situation is associated with differentiation [32]. H3K27me, catalyzed by EZH1 or EZH2 containing Polycomb Repressive Complex (PRC) 2, is a binding site for PRC1 to compact chromosomes [33]. KDM6A, KDM6B, and UTY have been identified as erasers of H3K27me [8].
A role of methylation on histone H3 lysine 36 (H3K36me) has initially been reported in the activation of genes in various systems [34]. However, H3K36me also functions in various processes, including alternative splicing [35], dosage compensation [36], DNA damage response [37], and transcriptional repression [38], depending on the chromatin context. H3K36me is tightly regulated by multiple KMTs and KDMs [20]. In vitro and in vivo studies, to date, have demonstrated that there are the following eight types of KMTs regulating H3K36 methylation levels in humans: SETD2, SETD3, NSD1, NSD2, NSD3, ASH1L, SMYD2, and SETMAR [20]. Although all H3K36-specific methyltransferases contain highly conserved SET domains, the patterns of H3K36 methylation vary. Most H3K36 KMTs preferentially mono- and di-methylate the residue, whereas SETD2 is the only enzyme that catalyzes H3K36me3 and requires mono- or di-methylated H3K36 for its function [39]. Conversely, methylated H3K36 can be demethylated by six KDMs. The H3K36 KDMs, which all belong to the Jumonji protein family, contain the conserved JmjC domain consisting of the following three groups: JHDM1 (KDM2A, KDM2B), JHDM3 (KDM4A, KDM4B, KDM4C), and RIOX1 [40]. JHDM1 is specific for H3K36me1/me2 demethylation, whereas JHDM3 uses H3K36 and H3K9 residues as substrates for the me2/me3-specific demethylation [41]. Similarly, in addition to H3K36me2/me3-specific activity, RIOX1 preferentially demethylates H3K4me1/me3 residues [42].
Histone H3 lysine 79 methylation (H3K79me) is associated with a diverse range of cellular processes including telomeric silencing, cellular development, cell-cycle checkpoint, DNA repair, and transcription regulation [43]. However, only one H3K79-specific KMT is known, with no KDM for H3K79 demethylation reported to date. DOT1L is the sole enzyme that is responsible for all three forms of H3K79 methylation in humans [44]. In addition, DOT1L is unique because it is the only non-SET domain containing methyltransferase, which has been identified to date [18].
Methylation on Histone H4 lysine 20 (H4K20me) displays various biological processes depending on its methylated levels. H4K20me1 is associated with transcriptional activation, appearing in the most highly transcribed group of genes with other core modifications at active promoters [45]. H4K20me2 has distinct roles, such as marking points of replication origin and damage response in the DNA [46,47]. Conversely, H4K20me3 is associated with transcriptional repression at promoters and silencing of repetitive DNA and transposons [45,48]. H4K20me is catalyzed by three enzymes, with activities restricted to specific methylation states. KMT5A, the first identified H4K20 methyltransferase, is the only H4K20me1 enzyme [49]. H4K20me1 can be further di- and tri-methylated by KMT5B and KMT5C [50]. Similarly, several distinct demethylases are involved in the removal of specific H4K20me. PHF8 acts as a demethylase for H4K20me1 [51]. Intriguingly, as previously described, PHF8 is the KDM that has additional activities towards H3K9me1 and H3K9me2 [8]. In addition, LSD1n, an alternatively spliced form of KDM1A, demethylates H4K20me1 and H4K20me2 [52], while PHF2 displays demethylase activity on H4K20me3 [53].

3. Neurodevelopmental Disorders Related with Histone Lysine Methylations

3.1. H3K4 Methylation

3.1.1. KMT2A and Wiedemann-Steiner Syndrome

Mutations in KMT2A were reported to be associated with Wiedemann-Steiner syndrome (WDSTS; OMIM 605130), an extremely rare neurodevelopmental condition accompanied by microcephaly, short stature, autism-like phenotype, and aggression [54]. Interestingly, these abnormal brain functions were recapitulated in KMT2A heterozygous mutant mice, which displayed profound deficits in long-term contextual fear memory [55,56]. In particular, neuronal ablation of KMT2A in the postnatal forebrain and adult prefrontal cortex exhibited increased anxiety and robust cognitive deficits in mice. In the same study, the analyzing H3K4me3 level and the gene expression profiles in KMT2A-deficient cortical neurons revealed that the homeodomain transcription factor, MEIS2, was repressed in these mice. Moreover, MEIS2 knockdown in prefrontal cortex phenocopied memory defects elicited by the deletion of KMT2A [57], thus proposing a critical role of MEIS2 in the pathogenesis of WDSTS.

3.1.2. KMT2D and Kabuki Syndrome 1

The most well-studied neurodevelopmental disorder associated with dysregulated H3K4me is Kabuki syndrome 1 (KABUK1; OMIM 147920), which is a rare congenital syndrome characterized by a distinctive face (a reminiscent of the make-up of actors Kabuki, traditional Japanese music-drama) and mental retardation with additional features including autism, seizure, and microcephaly [58]. Heterozygous mutations in KMT2D were found in more than 50% of patients with KABUK1, with the majority of mutations resulting in the premature termination of the protein product. In addition, mutations in KDM6A, an H3K27me demethylase gene, were also reported to contribute to less than 10% of this syndrome, and this type is referred as Kabuki syndrome 2 (KABUK2; OMIM 300867) [59,60,61,62]. Recently, Bögershausen et al. identified two mutations in RAP1A/B, which encode the Ras family small GTPases, in patients with KABUK1 by whole exome sequencing [61]. The authors also demonstrated that mutant RAP1 morphant phenocopied KDM6A and KMT2D mutants in zebrafish, and that the MEK/ERK pathway signaling was perturbed in RAP1- and KMT2D-defective cells. Interestingly, these phenotypes were rescued by treatment with an MEK inhibitor. On the other hands, the reduction in neurogenesis and hippocampal memory defects exhibited in a KABUK1 mouse model were ameliorated by the treatment with a histone deacetylase (HDAC) inhibitor, AR-42 [63]. Furthermore, a ketogenic diet rescued hippocampal memory defects through the elevation of beta-hydroxybutyrate, an endogenous HDAC inhibitor, in the same mice model [64]. Taken together, these results potentially provide diverse therapeutic directions to treat, or at least mitigate, the symptoms of KABUK1.

3.1.3. SETD1A and Schizophrenia

Extensive exome sequencing from over 200 patients with schizophrenia (SCZD; OMIM 181500) revealed two de novo mutations in SETD1A, which likely cause malfunction of SETD1A activity [65]. Furthermore, a strong association between the loss-of-function mutation of SETD1A and SCZD was confirmed by analyzing the whole exome sequencing of over 4000 patients with SCZD [66]. Interestingly, a recent bioinformatic analysis demonstrated that in addition to mutations in the protein coding region, mutations in the regulatory elements of SETD1A also contributed to the etiology of SCZD. De novo synonymous mutations within frontal cortex-derived DNase I-hypersensitive sites were enriched in SCZD, and SETD1A was identified as the highest statistical significant gene [67].

3.1.4. H3K4me Demethylases and Neurodevelopmental Disorders

Given the intimate association between H3K4 methylation and neurodevelopment disorders, it is rational to assume that KDMs that are responsible for demethylation of H3K4me can be also mutated in neurodevelopmental disorders. Indeed, homozygous missense mutation in KDM5A has been reported in an individual with intellectual disability [68]. Furthermore, KDM5C, another H3K4 demethylase coding gene, has been recurrently mutated in patients with mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ; OMIM 300534) [68,69,70]. Intriguingly, KDM5C has been shown to be transcriptionally regulated by ARX, a homeobox transcription factor, which is frequently mutated in X-linked mental retardation and epilepsy [71,72,73,74]. Additionally, a missense mutation in amine oxidase domain of KDM1A has been reported in patients with mixed features of KABUK1 and KBG syndrome (KBGS; OMIM 148050), which are characterized by macrodontia, distinctive craniofacial findings, and intellectual disability [75]. It is noteworthy that KDM1A catalyzes the demethylation of mono- and di-methylated H3K4, while other KDMs can demethylate H3K4me1/2/3 [76].

3.1.5. PHF21A and Potocki-Shaffer Syndrome

Besides H3K4me writers and erasers, PHF21A, an unmethylated H3K4 reader, was associated with a neurodevelopmental disorder. PHF21A was translocated in patients with Potocki-Shaffer syndrome (PSS; OMIM 601224), characterized by multiple exostoses, parietal foramina, intellectual disability, and craniofacial anomalies [77,78,79]. This translocation commonly results in deletion of the PHD domain coding region of PHF21A, suggesting that dictation of unmethylated H3K4 is crucial for its functions. Accordingly, the deficiency of head development was observed in PHF21A morpholino-injected zebrafish, and this defect was rescued by injection of human PHF21A mRNA [78]. In addition, PHF21A, in combination with KDM1A, is a key component of the BHC complex, which is involved in the repression of neuron-specific genes [80]. Furthermore, SCN3A, a KDM1A target gene, was derepressed, and LSD1 occupancy at the SCN3A promoter was reduced in PHF21A-translocated lymphoblastoid cell lines [78], hence proposing the idea that interplay between KDM1A and PHF21A is indispensable for normal brain development.

3.2. H3K9 Methylation

3.2.1. EHMT1 and Kleefstra Syndrome

Mutations in EHMT1, a gene encoding H3K9 methyltransferase, have been associated with Kleefstra syndrome (KS; OMIM 610253) which is characterized by intellectual disability, childhood hypotonia, and distinctive facial features [81,82]. Previously, this syndrome was known as the 9q Subtelomeric Deletion syndrome, in which minimal critical deleted region comprises EHMT1 [83]. In agreement with the role of EHMT1 on neurodevelopment in human, both Drosophila EHMT mutants and EHMT1 heterozygous knockout mice showed deficits in dendrite branching, learning, and memory [84,85]. Recent studies revealed the functions of EHMT1 in neurons, which may explain the phenotypes of patients and animal models of KS. A study measuring network and single cell activity in cortical cultures showed that EHMT1 is important for cortical neuronal network development [86]. Additionally, EHMT1 mediates homeostatic synaptic scaling, which stabilizes the activity of neural networks by balancing excitation and inhibition [87]. Interestingly, recent studies using exome sequencing revealed that the KS phenotypic spectrum was also linked to mutations in KMT2B and KMT2C [88,89], and these suggest that complicated epigenetic modules might underlie the pathogenesis of KS.

3.2.2. PHF8 and Siderius X-Linked Mental Retardation Syndrome

Siderius X-linked mental retardation syndrome (MRXSSD; OMIM 300263) is an X-linked intellectual disability condition; patients display mental retardation, a long face and broad nasal tip, and cleft lip and palate [90,91]. MRXSSD has been associated with mutations in PHF8 [91,92,93]. Interestingly, PHF8 has a histone lysine demethylase activity towards three different methylated lysines on histones, H3K9me1/2 and H4K20me1 [94,95,96], and also functions as a trimethylated H3K4 reader [94].
Loss of a PHF8 homolog in Caenorhabditis elegans resulted in axon guidance defects via the alteration of Hedgehog-like signaling [97]. Furthermore, injection of zebrafish PHF8 morpholino caused brain and craniofacial development defects [96], thus suggested a critical role of histone methylation dynamics regulated by PHF8 in MRXSSD. However, surprisingly, a recent study showed that Phf8-deficient mice had no obvious developmental defects and cognitive impairment, while Phf8-deficient primary cells had reduced the proliferative potential [98]. The results in mice indicated that MRXSSD is not simply caused by a single PFH8 mutation, but rather by its combination with other genetic or environmental factors at the same time. The different phenotypes exhibited by some animal models and varying degrees of intellectual disability of human patients with MRXSSD can be attributed to the various targets and complex functions of PHF8.

3.3. H3K27 Methylation

EZH2 and Weaver Syndrome

Weaver syndrome (WVS; OMIM 277590) is an autosomal dominant disorder characterized by overgrowth and intellectual disability [99,100,101]. Exome sequencing studies identified EZH2 as a causative gene of WVS [102,103]. EZH2 interacts with EED to form PRC2, which is an H3K27me3 methyltransferase complex [104]. Interestingly, mutations in EED were found in individuals displaying symptoms similar to those of WVS [14,105], suggesting that the dysregulation of H3K27 methylation is responsible for these symptoms.
Several studies have shown that EZH2 deficiencies in animal models induced abnormal neurogenesis in the cerebral cortex [106], cerebellum [107], and spinal cord [108] during embryonic development. Moreover, EZH2 is also implicated in adult hippocampal neurogenesis [109]. The alteration of neurogenesis induced by EZH2 deficiencies has been associated with various neurogenic processes, such as the reduction of neural progenitor cell proliferation [108,109,110], cell fate change [106,107,111,112,113], and neuronal migration [114,115,116]. These results suggest that EZH2-induced H3K27 methylation plays an important role in various processes of neurodevelopment, dysfunction of which might be closely related to intellectual disability in patients with WVS.

3.4. H3K36 Methylation

3.4.1. NSD1 Defects in Sotos Syndrome 1 and Beckwith-Wiedemann Syndrome

Recent studies demonstrated that disrupted levels or patterns of H3K36 methylation can cause a range of human diseases, including neurodevelopmental disorders. Among them, Sotos syndrome 1 (SOTOS1; OMIM 117550) represents an important human model system for studying the neurodevelopmental outcome of epigenetic dysregulation, which is caused by mutations in NSD1 [117]. SOTOS1 is an autosomal dominant disorder characterized by pre- and postnatal overgrowth, facial dysmorphism, macrocephaly, and non-progressive neurological delay [118]. Interestingly, amplified genomic events of NSD1 resulted in the opposite phenotypic outcome of SOTOS1, so that duplication in NSD1 led to reversed clinical phenotypes of SOTOS1 with microcephaly, as well as delayed bone age, indicating the importance of proper NSD1 expression during brain development [119]. In addition, it was shown that neuroblastoma and glioma may occur in human in the absence of NSD1 function [120]. Although the MAPK/ERK pathway was mapped as a downstream signaling pathway of NSD1-related overgrowth of stature in SOTOS1 [121], until recently, the molecular mechanisms how dysregulated NSD1 affects the mental retardation in SOTOS1 patients remains elusive. To date, two Sotos-like overgrowth syndromes called as Sotos syndrome 2 (SOTOS2; OMIM 614753) and 3 (SOTOS3; OMIM 617169) have been reported, which are caused by mutations in the NFIX and APC2 genes, respectively [122,123]. Among the products of the two genes, APC2, a WNT signaling pathway regulator, has recently been suggested as a crucial target of NSD1, of which defects may cause the intellectual disability associated with SOTOS [123]. In the mouse model system, Apc2 deficiency caused impaired learning and memory abilities along with an abnormal head shape. In addition, Nsd1 knockdown downregulated endogenous Apc2 expression, and defective neuronal phenotypes caused by the knockdown were rescued by the forced expression of Apc2, suggesting that APC2 may be a critical downstream gene of NSD1 in human neuronal cells.
Beckwith-Wiedemann syndrome (BWS; OMIM 130650) is another distinct overgrowth disorder with a broad clinical spectrum including hypoglycemia, ear creases/pits, cleft palate, and predisposition to embryonal tumors [124]. Martinez-y-Martinez et al. documented that mental retardation was observed in 6 of the 39 BWS cases [125]. It is well known that a major cause of BWS is the dysregulation of imprinted growth regulatory genes on chromosome 11p15 [126]. Interestingly, mutations in the NSD1 gene have been identified in 2 patients among 52 individuals clinically diagnosed with BWS, which suggests the involvement of NSD1 in imprinting of the 11p15 region [127].

3.4.2. NSD2 and Wolf-Hirshhorn Syndrome

NSD2 is one of the major genes associated with Wolf-Hirshhorn syndrome (WHS; OMIM 194190), of which key features include severe growth and mental retardation, microcephaly, “Greek helmet” facies, and closure defects [128]. Like patients with WHS, mice with Nsd2 gene deletions were growth-retarded, showed midline, craniofacial, and ocular anomalies [129]. However, these mice did not show any learning deficits [129]. Although the downstream effectors of NSD2, such as RUNX2 and p300, which are known to play a role in bone development [130], have been identified, the mechanism by which NSD2 deficiency causes neurological disorders in patients with WHS is still unknown.

3.5. H4K20 Methylation

Siderius X-Linked Syndromic Mental Retardation and Meier-Gorlin Syndrome 1

Thus far, two developmental diseases associated with dysregulated H4K20 methylation have been reported in human. As described above, one is MRXSSD (OMIM 300263) caused by mutations in PHF8, which encodes an eraser of H3K9 and H4K20 methylation. The other is Meier-Gorlin syndrome 1 (MGORS1; OMIM 224690) caused by homozygous or compound heterozygous mutation in the ORC1 gene [131], which encodes a specific reader of H4K20me2 [46]. MGORS1 is a rare disorder characterized by severe intrauterine, postnatal growth retardation, and microcephaly [132]. Interestingly, however, despite the presence of microcephaly, intellects of patients with MGORS1 are usually normal [133].

4. Perspectives

As reviewed above, the pathogenesis of various neurodevelopmental disorders is closely associated with alterations in histone methylation status, which, in many cases, can be primarily attributed to loss-of-function mutations in related factors. Given that histone methylation status is meticulously regulated by the balance between two opposing enzymes (i.e., KMTs and KDMs), pharmaceutical inhibition of specific targets counteracting the loss-of-function mutations responsible for diseases can be a possible therapeutic option. Interestingly, a subset of currently available psychotherapeutic drugs, such as the atypical antipsychotic Clozapine, the mood-stabilizer Valproate, and the antidepressant Phenelzine are known to interfere with histone methylation in the brain [134], although the relative contribution of this interference to their psychotherapeutic effects remains to be elucidated. In principle, an estimated 100 lysine and arginine residue-specific histone methyltransferases and demethylases [135] can be reasonable therapeutic targets, since they are considered more specific than HDACs [134]. Of note, histone methylation has been the most flourishing area of epigenetics research recently, and in line with this, huge efforts have been made to develop several potential therapeutic molecules, which specifically regulate histone methyltransferases and methylation reader proteins, particularly for cancer treatment [136]. For example, selective inhibitors, such as EPZ005687, GSK126, and EI1, which target EZH2 of PRC2, were recently reported by three independent groups to inhibit proliferation of B-cell lymphomas harboring EZH2-activating mutations [137,138,139]. In addition, tranylcypromine derivatives and polyaminoguanidine derivatives were designed and characterized to inhibit histone demethylases with potential anti-cancer activity [136]. Several epigenetic compounds, such as ORY-1001 and GSK2879552, are currently undergoing clinical trials for cancer treatment. If they meet the required biosafety standards, they could potentially be strong candidates for treating neurodevelopmental disorders, by correcting the impaired histone methylation status. Moreover, a microRNA-based gene silencing strategy targeting a specific histone methyltransferase or demethylase can be an alternative therapeutic option to consider in this regard. Indeed, several studies have reported the important roles of miRNA in histone methylation and following transcriptional gene silencing in various model systems [140,141,142]. Although further research is warranted, it will be interesting to establish whether these epigenetic compounds and/or microRNA-based specific gene silencing approaches have obvious therapeutic benefits for the patients with the neurodevelopmental disorders outlined in this review.

Acknowledgments

This work was supported by the DGIST R&D and MIREBraiN program, Basic Science Research Program through the ministry of science, ICT & future planning of Korea (17-BD-0402, 17-BT-02, and 17-01-HRSS-02); the Development of Platform Technology for Innovative Medical Measurements Program from the Korea Research Institute of Standards and Science (KRISS-2017-GP2017-0020) (Sung Bae Lee); the Basic Science Research Program of the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (NRF-2014R1A1A2056768 and NRF-2017R1A2B4004241 Kyoung Sang Cho), and NRF-2014R1A1A3051462) (Im-Soon Lee); the Korea Health Technology Research & Development Project, Ministry of Health & Welfare, Republic of Korea (HI12C1472) (Kyoung Sang Cho); and KRIBB initiative program (Jeong-Hoon Kim).

Author Contributions

Sung Bae Lee and Kyoung Sang Cho designed the review; and Jeong-Hoon Kim, Jang Ho Lee, Im-Soon Lee, Sung Bae Lee and Kyoung Sang Cho wrote the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

APC2Adenomatosis polyposis coli 2
ARXAristaless related homeobox
ASH1LASH1 like histone lysine methyltransferase
BHC complexBRAF35/histone deacetylase complex
BWSBeckwith-Wiedemann syndrome
DOT1LDOT1 like histone lysine methyltransferase
EEDEmbryonic ectoderm development
EHMT1Euchromatic histone lysine methyltransferase 1
EHMT2Euchromatic histone lysine methyltransferase 2
ERKExtracellular signal-regulated kinase
ESCEmbryonic stem cells
EZH1Enhancer of zeste 1 polycomb repressive complex 2 subunit
EZH2Enhancer of zeste 2 polycomb repressive complex 2 subunit
FADFlavin adenosine dinucleotide
H3K4Histone H3 lysine 4
H3K4meMethylation on histone H3 lysine 4
H3K9Histone H3 lysine 9
H3K9meMethylation on histone H3 lysine 9
H3K27Histone H3 lysine 27
H3K27meMethylation on histone H3 lysine 27
H3K36Histone H3 lysine 36
H3K36meMethylation on histone H3 lysine 36
H3K79Histone H3 lysine 79
H3K79meMethylation on histone H3 lysine 79
H3R2Histone H3 arginine 2
H3R8Histone H3 arginine 8
H3R17Histone H3 arginine 17
H3R26Histone H3 arginine 26
H4K20Histone H4 lysine 20
H4K20meMethylation on histone H4 lysine 20
H4R3Histone H4 arginine 3
HDACHistone deacetylase
HP1Heterochromatin protein 1
JHDMJmjC-domain containing histone demethylases
JmjCJumonji C
KABUK1Kabuki syndrome 1
KABUK2Kabuki syndrome 2
KBGSKBG syndrome
KSKleefstra syndrome
LSD1nLysine-specific demethylase 1 variant
KDMLysine demethylase
KMTLysine methyl transferase
MAPKMitogen-activated protein kinase
MEIS2Myeloid ecotropic viral integration site 1 homolog 2
MEKMitogen-activated protein kinase kinase
MGORS1Meier-Gorlin syndrome 1
MRXSCJMental retardation, X-linked, syndromic, Claes-Jensen type
MRXSSDSiderius X-linked mental retardation syndrome
NFIXNuclear factor I X
NSD1Nuclear receptor-binding SET domain protein 1
NSD2Nuclear receptor-binding SET domain protein 2
NSD3Nuclear receptor-binding SET domain protein 3
ORC1Origin recognition complex subunit 1
PHF2PHD finger protein 2
PHF21APHD finger protein 21A
PHF8PHD finger protein 8
PRC1Polycomb repressive complex 1
PRC2Polycomb repressive complex 2
PRDMPR/SET domain family
PSSPotocki-Shaffer syndrome
RAP1A/BRAS-related protein 1A/B
RIOX1Ribosomal oxygenase 1
RUNX2Runt related transcription factor 2
SCZDSchizophrenia
SCN3ASodium voltage-gated channel alpha subunit 3
SETD1ASET domain containing 1A
SETD1BSET domain containing 1B
SETD2SET domain containing 2
SETD3SET domain containing 3
SETDB1SET domain bifurcated 1
SETMARSET domain and mariner transposase fusion gene
SMYD2SET and MYND domain containing 2
SOTOS1Sotos syndrome 1
SOTOS2Sotos syndrome 2
SOTOS3Sotos syndrome 3
SUV39H1Suppressor of variegation 3-9 homolog 1
SUV39H2Suppressor of variegation 3-9 homolog 2
UTYUbiquitously transcribed tetratricopeptide repeat containing, Y-linked
WDSTSWiedemann-Steiner syndrome
WHSWolf-Hirshhorn syndrome
WVSWeaver syndrome

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Ijms 18 01404 g001 550
Figure 1. Histone methylation and neurodevelopmental disorders: (a) histone methylation sites in the tails of histone H3 and H4; and (b) histone methyltransferases, demethylases, and methylated histone binding proteins linked with neurodevelopmental disorders. Five methylation sites were associated with several neurodevelopmental disorders. BWS, Beckwith-Wiedemann syndrome; KABUK1/2, Kabuki syndrome 1/2; KBGS, KBG syndrome; KS, Kleefstra syndrome; MGORS1, Meier-Gorlin syndrome 1; MRXSCJ, Mental retardation, X-linked, syndromic, Claes-Jensen type; MRXSSD, Siderius X-linked mental retardation syndrome; PSS, Potocki-Shaffer syndrome; SCZD, Schizophrenia; SOTOS1, Sotos syndrome 1; WDSTS, Wiedemann-Steiner syndrome; WHS, Wolf-Hirshhorn syndrome; WVS, Weaver syndrome.
Figure 1. Histone methylation and neurodevelopmental disorders: (a) histone methylation sites in the tails of histone H3 and H4; and (b) histone methyltransferases, demethylases, and methylated histone binding proteins linked with neurodevelopmental disorders. Five methylation sites were associated with several neurodevelopmental disorders. BWS, Beckwith-Wiedemann syndrome; KABUK1/2, Kabuki syndrome 1/2; KBGS, KBG syndrome; KS, Kleefstra syndrome; MGORS1, Meier-Gorlin syndrome 1; MRXSCJ, Mental retardation, X-linked, syndromic, Claes-Jensen type; MRXSSD, Siderius X-linked mental retardation syndrome; PSS, Potocki-Shaffer syndrome; SCZD, Schizophrenia; SOTOS1, Sotos syndrome 1; WDSTS, Wiedemann-Steiner syndrome; WHS, Wolf-Hirshhorn syndrome; WVS, Weaver syndrome.
Ijms 18 01404 g001
Table
Table 1. The names of the histone methylation-related factors mentioned in this paper and their synonyms.
Table 1. The names of the histone methylation-related factors mentioned in this paper and their synonyms.
SymbolPrevious SymbolSynonym(s)ResidueFunction
ASH1LASH1LASH1, ASH1L1, huASH1, KMT2HH3K36Methyltransferase
DOT1LDOT1L DOT1, KIAA1814, KMT4H3K79Methyltransferase
EHMT1EHMT1bA188C12.1, Eu-HMTase1, FLJ12879, KIAA1876, KMT1DH3K9Methyltransferase
EHMT2BAT8, C6orf30Em:AF134726.3, G9A, KMT1C, NG36/G9aH3K9Methyltransferase
EZH1EZH1KIAA0388, KMT6B H3K27Methyltransferase
EZH2EZH2ENX-1, EZH1, KMT6, KMT6AH3K27Methyltransferase
KDM1AAOF2, KDM1BHC110, KIAA0601, LSD1H3K4, H3K9, H4K20Demethylase
KDM2AFBXL11, KDM2ACXXC8, DKFZP434M1735, FBL11, FBL7, FLJ00115, JHDM1A, KIAA1004, LILINAH3K36Demethylase
KDM2BFBXL10, KDM2BCXXC2, Fbl10, JHDM1B, PCCX2H3K36Demethylase
KDM3AJMJD1, JMJD1A, KDM3AJHMD2A, KIAA0742, TSGAH3K9Demethylase
KDM3BC5orf7, JMJD1B, KDM3BKIAA1082, NET22 H3K9Demethylase
KDM4AJMJD2, JMJD2A, KDM4AJHDM3A, KIAA0677, TDRD14AH3K9, H3K36Demethylase
KDM4BJMJD2B, KDM4BKIAA0876, TDRD14B H3K9, H3K36Demethylase
KDM4CJMJD2C, KDM4CGASC1, KIAA0780, TDRD14CH3K9, H3K36Demethylase
KDM5AJARID1A, KDM5A, RBBP2-H3K4Demethylase
KDM5CJARID1C, KDM5C, MRX13, SMCXDXS1272E, XE169 H3K4Demethylase
KDM6AKDM6A, UTX-H3K27Demethylase
KDM6BJMJD3, KDM6BKIAA0346H3K27Demethylase
KMT2AKMT2A, MLLALL-1, CXXC7, HRX, HTRX1, MLL1A, TRX1H3K4Methyltransferase
KMT2BKMT2BCXXC10, HRX2, KIAA0304, MLL1B, MLL2, MLL4, TRX2, WBP7H3K4Methyltransferase
KMT2CKMT2C, MLL3HALR, KIAA1506H3K4Methyltransferase
KMT2DKMT2D, MLL2, TNRC21ALR, CAGL114, MLL4H3K4Methyltransferase
KMT5AKMT5A, SETD8PR-Set7, SET07, SET8H4K20Methyltransferase
KMT5BKMT5B, SUV420H1CGI-85H4K20Methyltransferase
KMT5CKMT5C, SUV420H2MGC2705H4K20Methyltransferase
NSD1STOARA267, FLJ22263, KMT3BH3K36Methyltransferase
NSD2WHSC1KMT3G, MMSETH3K36Methyltransferase
NSD3WHSC1L1FLJ20353, KMT3F, WHISTLE H3K36Methyltransferase
ORC1ORC1LHSORC1, PARC1H4K20Recognition
PHF2-CENP-35, JHDM1E, KDM7C, KIAA0662H3K9, H4K20Demethylase
PHF8-JHDM1F, KDM7B, KIAA1111, ZNF422H3K9, H4K20/H3K4Demethylase/Recognition
PHF21A-BHC80, BM-006, KIAA1696H3K4Recognition
RIOX1C14orf169 FLJ21802, JMJD9, MAPJD, NO66H3K4, H3K36Demethylase
SETD1A-KIAA0339, KMT2F, Set1H3K4Methyltransferase
SETD1B-KIAA1076, KMT2G, Set1B H3K4Methyltransferase
SETD2-FLJ23184, HIF-1, HYPB, KIAA1732, KMT3AH3K36Methyltransferase
SETD3C14orf154FLJ23027H3K4, H3K36Methyltransferase
SETDB1SETDB1ESET, KG1T, KIAA0067, KMT1E, TDRD21 H3K9Methyltransferase
SETMAR-MentaseH3K4, H3K36Methyltransferase
SMYD2-HSKM-B, KMT3C, ZMYND14H3K4, H3K36Methyltransferase
SUV39H1SUV39H KMT1AH3K9Methyltransferase
SUV39H2SUV39H2KMT1B FLJ23414 H3K9Methyltransferase
UTYUTYKDM6AL, KDM6C H3K27Demethylase
The names of the proteins are followed by HUGO Gene Nomenclature Committee (http://www.genenames.org/)
Table
Table 2. Neurodevelopmental disorders caused by mutations in histone methylation-related genes.
Table 2. Neurodevelopmental disorders caused by mutations in histone methylation-related genes.
DisorderOMIMSymptomGeneResidueFunction
Beckwith-Wiedemann syndrome (BWS)130650Pediatric overgrowth disorder involving a predisposition to tumor developmentNSD1H3K36Methyltransferase
Kabuki syndrome 1147920Congenital mental retardation, postnatal dwarfism, peculiar faces, broad and depressed nasal tip, large prominent earlobes, cleft or high-arched palate, scoliosis, short fifth finger, and persistence of finger padsKMT2D KDM6AH3K4 H3K27Methyltransferase Demethylase
Kabuki syndrome 2 (KABUK1/2)300867
KBG syndrome (KBGS)148050Macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, neurologic involvement that includes global developmental delay, seizures, and intellectual disabilityKDM1AH3K4 H3K9 H4K20Demethylase Demethylase Demethylase
Kleefstra syndrome (KS)610253Severe mental retardation, hypotonia, epileptic seizures, flat face with hypertelorism, synophrys, anteverted nares, everted lower lip, carp mouth with macroglossia, and heart defectsKMT2B, KMT2C EHMT1H3K4 H3K4 H3K9Methyltransferase Methyltransferase Methyltransferase
Meier-Gorlin syndrome 1 (MGORS1)224690Severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellaeORC1H4K20Recognition
Mental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ)300534Severe mental retardation, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasiaKDM5CH3K4Demethylase
Potocki-Shaffer syndrome (PSS)601224Craniofacial abnormalities, developmental delay, intellectual disability, multiple exostoses, and biparietal foraminaPHF21AH3K4Recognition
Schizophrenia (SCZD)181500Hallucinations and delusions, severely inappropriate emotional responses, disordered thinking and concentration, erratic behavior, as well as social and occupational deteriorationSETD1AH3K4Methyltransferase
Siderius X-linked mental retardation syndrome (MRXSSD)300263Mental retardation, a repaired cleft lip, a long face with broad nasal tip, long hands with long thin fingers, and flat feet with long thin toesPHF8H3K4 H3K9 H4K20Recognition Demethylase Demethylase
Sotos syndrome 1 (SOTOS1)117550Excessively rapid growth, acromegalic features, and non-progressive cerebral disorder with mental retardationNSD1H3K36Methyltransferase
Weaver syndrome (WVS)277590Pre- and postnatal overgrowth, accelerated osseous maturation, characteristic craniofacial appearance, and developmental delay, broad forehead and face, ocular hypertelorism, prominent wide philtrum, micrognathia, deep horizontal chin groove, and deep-set nailsEZH2H3K27Methyltransferase
Wiedemann-Steiner syndrome (WDSTS)605130Hypertrichosis cubiti associated with short stature, consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, down slanting and vertically narrow palpebral fissures, mild to moderate intellectual disability, behavioral difficulties, and hypertrichosis on the backKMT2AH3K4Methyltransferase
Wolf-Hirschhorn syndrome (WHS)194190Pre- and postnatal growth deficiency, developmental disability of variable degree, characteristic craniofacial features, and a seizure disorderNSD2H3K36Methyltransferase

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Kim, J.-H.; Lee, J.H.; Lee, I.-S.; Lee, S.B.; Cho, K.S. Histone Lysine Methylation and Neurodevelopmental Disorders. Int. J. Mol. Sci. 2017, 18, 1404. https://doi.org/10.3390/ijms18071404

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Kim J-H, Lee JH, Lee I-S, Lee SB, Cho KS. Histone Lysine Methylation and Neurodevelopmental Disorders. International Journal of Molecular Sciences. 2017; 18(7):1404. https://doi.org/10.3390/ijms18071404

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Kim, Jeong-Hoon, Jang Ho Lee, Im-Soon Lee, Sung Bae Lee, and Kyoung Sang Cho. 2017. "Histone Lysine Methylation and Neurodevelopmental Disorders" International Journal of Molecular Sciences 18, no. 7: 1404. https://doi.org/10.3390/ijms18071404

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