Hum Genet (2013) 132:359–383 DOI 10.1007/s00439-013-1271-x

REVIEW PAPER

Genetic syndromes caused by mutations in epigenetic genes

Marı´a Berdasco • Manel Esteller

Received: 10 December 2012 / Accepted: 18 January 2013 / Published online: 31 January 2013 Ó Springer-Verlag Berlin Heidelberg 2013

Abstract The orchestrated organization of epigenetic epigenetic alterations increases. As recent examples, muta- factors that control chromatin dynamism, including DNA tions of histone demethylases and members of the non- methylation, histone marks, non-coding RNAs (ncRNAs) coding RNA machinery have recently been associated with and chromatin-remodeling proteins, is essential for the Kabuki syndrome, Claes-Jensen X-linked mental retardation proper function of tissue homeostasis, cell identity and syndrome and Goiter syndrome. In this review, we describe development. Indeed, deregulation of epigenetic profiles the variety of germline mutations of epigenetic modifiers that has been described in several human pathologies, including are known to be associated with human disorders, and dis- complex diseases (such as cancer, cardiovascular and cuss the therapeutic potential of epigenetic drugs as pallia- neurological diseases), metabolic pathologies (type 2 dia- tive care strategies in the treatment of such disorders. betes and obesity) and imprinting disorders. Over the last decade it has become increasingly clear that mutations of genes involved in epigenetic mechanism, such as DNA Introduction methyltransferases, methyl-binding domain proteins, his- tone deacetylases, histone methylases and members of the Chromatin dynamism is critical to basic cellular processes SWI/SNF family of chromatin remodelers are linked to such as gene transcription, DNA replication, DNA human disorders, including Immunodeficiency Centro- recombination and DNA repair. DNA accessibility is meric instability Facial syndrome 1, Rett syndrome, modulated by epigenetic mechanisms that ultimately alter Rubinstein–Taybi syndrome, Sotos syndrome or alpha- the structure of the chromatin and provide binding sites thalassemia/mental retardation X-linked syndrome, among for a wide variety of regulatory proteins. The orchestrated others. As new members of the epigenetic machinery are organization of epigenetic factors, including DNA meth- described, the number of human syndromes associated with ylation, histone marks, non-coding RNAs (ncRNAs), and their associated chromatin proteins, is essential for development and cellular differentiation. For instance, M. Berdasco M. Esteller (&) extensive chromatin remodeling occurs on a global level Cancer Epigenetics Group, Cancer Epigenetics and Biology during early development. DNA methylation patterns Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 3rd Floor, Hospital Duran i Reynals, Av. Gran undergo genome-wide alterations that occur immediately Via 199-203, 08908 L’Hospitalet de LLobregat Barcelona, after fertilization and during early-preimplantation devel- Catalonia, Spain opment, together with histone modification changes, such e-mail: [email protected] as increased H3K9me with differentiation (Reik 2007). M. Esteller Epigenetic factors also guarantee the activation and Department of Physiological Sciences II, School of Medicine, maintenance of specific differentiation programs in adult University of Barcelona, Barcelona, Catalonia, Spain somatic cells (Berdasco and Esteller 2010). The active role of epigenetic factors in controlling cellular differen- M. Esteller Institucio´ Catalana de Recerca I Estudis Avanc¸ats (ICREA), tiation is supported by spontaneous cell differentiation 08010 Barcelona, Catalonia, Spain after treatment with demethylating agents or histone 123 360 Hum Genet (2013) 132:359–383 deacetylase inhibitors (reviewed in Berdasco and Esteller (deoxycytidine-phosphate-deoxyguanosine) sites located 2011). Treatment with the demethylation agent 5-aza-20- throughout the genome, but there are certain areas, known deoxycytidine promotes differentiation of different types as CpG islands, that are enriched in CpG dinucleotides of adult stem cells into cardiac myogenic or osteogenic (especially in promoter regions). Non-CpG islands of the cells by enhancing the expression of lineage genes. In a human genome are usually methylated and prevent geno- similar manner, histone deacetylase inhibitor trichostatin mic instability phenomena, such as the movement of enhances chondrogenic or neural differentiation of stem transposable elements (Berdasco and Esteller 2010). Nor- cells, reinforcing the epigenetic control of differentiation. mal methylation at these sequences is also necessary for Furthermore, the essential role of these factors is reflected X-chromosome inactivation in females and genomic in the fact that altered profiles of epigenetic marks often imprinting. Conversely, CpG islands are usually unme- lead to defaults in cellular homeostasis and development thylated, being closely related to the expression of house- of human diseases. Genetic alterations could explain the keeping genes. It is estimated that only 6 % of the human causes of several monogenic diseases. However, the CpG islands are methylated and, consequently, silenced, genetic basis underlying the origin of complex and mul- being essential for maintaining tissue-specific patterns tifactorial diseases remains largely unknown and the during development and differentiation. By our current importance of the role of non-genetic mechanisms, understanding, this ‘‘DNA methylation code’’ seems to be including epigenetic mechanisms or posttranslational an oversimplification, since, in recent years, new genomic protein modifications, is increasingly being realized. contexts outside of CpG islands, known as CpG shores, Cancer has been the best characterized complex human have emerged as candidates for regulating gene expression disease associated with epigenetic defects (Berdasco and of tissue-specific genes. The technological advance in Esteller 2010), but the list of complex diseases carrying studying DNA methylation will provide insight into the epigenetic defaults has been increasing rapidly in recent role of 5-methylcytosine patterns with respect to their years. Epigenetic studies have now been made of complex density, location and function, amongst other features. diseases such as obesity, type 2 diabetes mellitus, car- Additionally the recently discovered cytosine modification diovascular diseases and neurological disorders. These 5-hydroxymethyl-20-deoxycytidine (5hmC) needs to be pathogenic mechanisms are particularly interesting further studied to determine its implications for normal and because the epigenetic effects may also be affected by diseased epigenetic regulation. aspects of the environment such as diet and lifestyle, The enzymes responsible for introducing the methyl raising the possibility of ‘‘resetting’’ the altered epigenetic group into a cytosine are DNA methyltransferases marks. Deleterious epigenetic profiles could be a conse- (DNMTs). Three major proteins with DNMT activity have quence of mutations in the ‘‘writers’’, that is to say, been identified in mammals: DNMT1, DNMT3A and dysfunctional enzymes that are responsible for putting in DNMT3B. DNMT1 is a widely expressed maintenance and out the epigenetic marks. Defective epigenetic DNMT that recognizes hemimethylated DNA and is machinery has been observed in cancer initiation and responsible for maintaining the existing methylation pat- progression. Furthermore, germline mutations of epige- terns after DNA replication. By contrast, DNMT3 enzymes netic modifiers contribute to the development of human are de novo DNMTs that introduce methyl groups into diseases including intellectual disability (review in: Fro- previously unmethylated cytosines. These enzymes intro- yen et al. 2006; Kramer and van Bokhoven 2009; duce a methyl group into the genome, but this ‘‘writing’’ Franklin and Mansuy 2011). The aim of the present must be interpreted (read) by the rest of the cellular review is to provide an overview of these disorders machinery (i.e., transcription factors, DNA polymerases, grouped by the type of epigenetic change involved: chromatin-remodeling proteins, epigenetic enzymes, etc.). (i) alterations in DNA methylation players; (ii) mutations Additional members of the DNMT family without meth- in histone modifiers; (iii) disruption of chromatin-remod- yltransferase activity have been reported, such as DNMT2 eling complexes, and (iv) mutations in non-coding RNA or DNMT3L. DNMT3L lacks the amino acid sequence processing machinery. necessary for methyltransferase but it seems to be required for the establishment of maternal genomic imprints (Aapola et al. 2002). Genetic disorders linked to DNA methylation defects Methyl-CpG-binding domain (MBD) proteins are one of the DNA methylation-associated proteins that could be DNA methylation, or the addition of a methyl group to a recruited to methylated DNA and in turn facilitate the cytosine, is a key epigenetic player that has long been recruitment of histone modifiers and chromatin-remodeling considered the genome’s fifth base (Portela and complexes (Portela and Esteller 2010). Evidence is Esteller 2010). In mammals this reaction occurs at CpG mounting of the role of DNA methylation in modulating 123 Hum Genet (2013) 132:359–383 361 cognitive functions of the central nervous system, such as DNMT3 mutations and immunodeficiency centromeric learning and memory, and of how dysregulation of DNMTs instability facial syndrome 1 activities can give rise to neurological disorders (Liu et al. 2009; Urdinguio et al. 2009; Feng et al. 2010). Some of the Immunodeficiency centromeric instability facial syndrome genetic syndromes featuring mutations in the DNA-related 1 (ICF1, MIM #242860) is a rare autosomal recessive machinery that often cause neurological disorders are dis- disorder characterized by immune defects in association cussed in this section (Table 1). with centromere instability and facial anomalies. Several chromosomal abnormalities have been described, including DNMT1 mutations and disorders of the central the juxtacentromeric heterochromatin formation of chro- and peripheral nervous system mosomes 1, 9 and 16, an increased frequency of somatic recombination between the arms of these chromosomes, Hereditary sensory and autonomic neuropathy type 1 with and a marked tendency to form multibranched configura- dementia and hearing loss (HSAN1; MIM #614116) is a tions (Ehrlich 2003). 60 % of ICF1 patients carry muta- degenerative disorder of the central and peripheral nervous tions in the de novo DNA methyltransferase DNMT3B system. Its clinical manifestations consist of sensory (Xu et al. 1999; Lana et al. 2012). Mutations in the ZBTB24 impairment, sudomotor dysfunction (loss of sweating), gene, which encodes a transcription factor, are responsible dementia and sensorineural hearing loss. HSAN1 is for the ICF type 2 phenotype (de Greef et al. 2011). inherited in an autosomal dominant manner, although the Hypomethylation in ICF patients commonly affect specific proportion of patients with de novo mutations is unknown, non-coding repetitive sequences (satellites 2 and 3, subt- DNMT1 being the only gene in which mutations of exons elomeric sequences and Alu sequences), imprinted genes 20 and 21 are known to cause HSAN1 (Klein et al. 2011; and genes located in constitutive and facultative hetero- Winkelmann et al. 2012). Molecular genetic testing to chromatin (Xu et al. 1999; Yehezkel et al. 2008; Brun et al. screen for three mutations in exon 21 of DNMT1 2011), causing chromatin decondensation and chromosome (p.Ala570Val, p.Gly605Ala and p.Val606phe) is available instability. Recently, whole-genome bisulfite sequencing of for research purposes. Mutations are present within the an ICF patient harboring mutated DNMT3B and one heal- targeting-sequence domain of DNMT1 that regulates the thy control have been performed to assess DNA methyla- binding of the enzyme to chromatin during the S-phase and tion at base pair resolution (Heyn et al. 2012). The authors is responsible for maintaining this association during the concluded that ICF patients have 42 % less global DNA G2-M phases (Fatemi et al. 2001; Song et al. 2012). methylation, especially in inactive heterochromatic regions DNMT1 is strongly expressed in postmitotic neurons and (in accordance with previous studies). Interestingly, the plays important roles in neuronal differentiation, migration methylation status of transcriptional active loci and rRNA and central neural connection (Feng et al. 2010). The repeats did not change, suggesting that there is a selective functional involvement of DNMT1 mutations has been pressure to maintain the stability of these genomic struc- assessed in in vitro studies in HeLa cells (Klein et al. tures (Heyn et al. 2012). In addition to methylation studies, 2011), so that cells carrying mutations in the DNMT1 the altered expression of more than 700 genes in ICF1 targeting sequence showed abnormal heterochromatin patients has been described, especially genes related to binding of DNMT1 during the G2 phase and were pre- immune function, development and neurogenesis (Jin et al. maturely degraded. Abolishing DNMT1 function affects 2008). Interestingly, half the upregulated genes were hy- DNA methylation cellular levels: first, a lower level of pomethylated (compared with normal cells) in parallel with global methylation (8 %) has been measured in mutant the loss of the histone repressive H3K27 trimethylation cells (i.e., satellite 2 methylation was reduced); second, mark and the gain of the histone active marks H3K9 site-specific hypermethylation at specific loci has also been acetylation and H3K4 trimethylation (Jin et al. 2008). Not found (Klein et al. 2011). Additionally, DNMT1 is required only the protein-coding genes are altered; a dramatic loss for CD4? differentiation into T regulatory cells (Jose- of methylation (from 80 to 30 %) was found in hetero- fowicz et al. 2009), and a link between the absence of chromatic genes, which are usually aberrantly hypome- CD4? T regulatory cells and the autoimmune response in thylated in cancer cells, although the hypomethylation was neurological syndromes has been proposed (Winkelmann not always associated with their activation (Brun et al. et al. 2012). The findings from several studies together 2011). In contrast to the dysregulation of protein-coding suggest that DNMT1 participates in a precise mechanism genes, no changes in histone marks associated with het- of dynamic regulation of neuronal survival, but additional erochromatic genes could be found (Brun et al. 2011). efforts will be needed to elucidate its pathogenic mecha- Finally, the genomic instability generated in ICF patients nisms and to explain the phenotypic variation observed also resulted in replication defects, including shortening of between individuals bearing different mutations. the S-phase, a higher global replication fork speed and 123 362 Hum Genet (2013) 132:359–383

Table 1 List of human disorders associated with germline mutations in epigenetic genes Gene GeneIDa Cytogenetic Function Disease OMIMb References location

Mutations associated with DNA methylation DNMT1 1786 19p13.2 DNMT Hereditary sensory and autonomic neuropathy type 1 614116 Klein et al. (2011), (HSAN1) Winkelmann et al. (2012) DNMT3b 1789 20q11.21 DNMT Immunodeficiency–centromeric instability–facial 242860 Xu et al. (1999); anomalies syndrome 1 (ICF1) Lana et al. (2012) MECP2 4204 Xq28 MDB Rett syndrome 312750 Amir et al. (1999), Moretti and Zoghbi (2006) MECP2 4204 Xq28 MDB Angelman syndrome 105830 Watson et al. (2001) Mutations associated with histone modifications MYST4 23522 10q22.2 HAT Genitopatellar syndrome 606170 Campeau et al. (2012a), Simpson et al. (2012) MYST4 23522 10q22.2 HAT Say-Barber-Biesecker-Young-Simpson syndrome 603736 Clayton-Smith et al. (SBBYS) (2011) CREBBP 1387 16p13.3 HAT Rubinstein–Taybi syndrome 1 180849 Petrij et al. (1995), Tsai et al. (2011) EP300 2033 22q13.2 HAT Rubinstein–Taybi syndrome 2 613684 Arany et al. (1994), Bartsch et al. (2010) HDAC4 14063 2q37.3 HDAC Brachydactyly-mental retardation syndrome 600430 Williams et al. (BDMR) (2010), Morris et al. (2012) EHMT1 79813 9q34.3 HMT Kleefstra syndrome 610253 Kleefstra et al. (2009) EZH2 2146 7q36.1 HMT Weaver syndrome 2 (WVS2) 614421 Gibso et al. (2012) MLL2 8085 12q13.12 HMT Kabuki syndrome 1 147920 Ng et al. (2010), Hannibal et al. (2011) NSD1 64324 5q35.2 HDMT Sotos syndrome 117550 Tatton-Brown and Rahman (2007) NSD1 64324 5q35.2 HDMT Weaver syndrome 1 (WVS1) 277590 Douglas et al. (2003) NSD1 64324 5q35.2 HDMT Beckwith–Wiedemann syndrome 130650 Baujat et al. (2004) JMJD3 7403 Xp11.3 HDMT Kabuki syndrome 2 300867 Lederer et al. (2012) PHF8 23133 Xp11.22 HDMT Siderius X-Linked Mental Retardation Syndrome 300263 Laumonnier et al. (MRXSSD) (2005), Koivisto et al. (2007) JARID1C 8242 Xp11.22 HDMT Claes-Jensen X-linked Mental retardation syndrome 300534 Claes et al. (2000), Jensen et al. (2005) Mutations associated with chromatin- remodeling factors ATXN7 6314 3p14.1 STAGA- Spinocerebellar ataxia 7 164500 Garden and La HAT Spada (2008) complex ATRX 546 Xq21.1 SWI/SNF Alpha-thalassemia X-linked mental retardation 301040 Gibbons et al. (1995) complex syndrome ATRX 546 Xq21.1 SWI/SNF Mental retardation-hypotonic facies syndrome, 309580 Abidi et al. (2005) complex X-linked ATRX 546 Xq21.1 SWI/SNF Alpha-thalassemia myelodysplasia syndrome 300448 Gibbons et al. (2003) complex ERCC6 2074 10q11.23 SWI/SNF Cockayne syndrome, type B (CSB) 133540 Laugel et al. (2010) complex ERCC8 1161 5q12.1 SWI/SNF Cockayne syndrome, type A (CSA) 216400 Henning et al. (1995) complex

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Table 1 continued Gene GeneIDa Cytogenetic Function Disease OMIMb References location

SMARCB1 6598 22q11.23 SWI/SNF Coffin-Siris syndrome 135900 Tsurusaki et al. complex (2012) SMARCA4 6597 19p13.2 SWI/SNF Coffin-Siris syndrome 135900 Tsurusaki et al. complex (2012) SMARCA2 6596 9p24.3 SWI/SNF Coffin-Siris syndrome 135900 Tsurusaki et al. complex (2012) SMARCA2 6596 9p24.3 SWI/SNF Nicolaides-Baraitser syndrome 601358 Van Houdt et al. complex (2012) ARID1A 8289 1p36.11 SWI/SNF Coffin-Siris syndrome 135900 Tsurusaki et al. complex (2012) ARID1B 57492 6q25.3 SWI/SNF Coffin-Siris syndrome 135900 Tsurusaki et al. complex (2012) SRCAP 10847 16p11.2 SRCAP Floating-Harbor syndrome 136140 Hood et al. complex (2012) CDH7 55636 8q12.1 CHD Coloboma of the eye, Heart Anomaly, choanal 214800 Sanlaville et al. complex Atresia, Retardation, Genital And Ear Anomalies (2006) syndrome (CHARGE) CDH7 55636 8q12.1 CHD Hypogonadotropic hypogonadism 2 with or without 147950 Kim et al. complex anosmia (2008) Mutations associated with non-coding RNAs DICER1 23405 14q32.13 miRNA Goiter, multinodular 1, with or without Sertoli- 138800 Rio Frio et al. processing Leydig cell tumors (2011) TDP-43 23435 1p36.22 miRNA Amyotrophic lateral sclerosis 612069 Ling et al. processing (2010) FMRP 2332 Xq27.3 miRNA Fragile X syndrome 300624 Edbauer et al. processing (2010) DGCR8 54487 22q11.21 miRNA DiGeorge syndrome 188400 Shiohama et al. processing (2003), Stark et al. (2008) CHD chromodomain helicase DNA-binding protein, DNMT DNA methyltransferase, HAT histone acetyltransferase, HDAC histone deacetylase, HDMT histone demethylase, MDB methyl DNA-binding domain protein, HMT histone methyltransferase, SRCAP Snf2-related CREBBP activator protein, STAGA SPT3/TAF9/GCN5 transcription coactivator complex, SWI/SNF SWItch/sucrose non fermentable a Identification in Entrez Gene database (http://www.ncbi.nlm.nih.gov/gene) b Identification in Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim/) earlier replication of heterochromatic genes in S-phase 2012). It affects predominantly females, occurring at a (Lana et al. 2012). To conclude, the loss of DNMT3B frequency of 1:10,000 live births, but male patients with function and the interaction of DNMT3B with histone Rett syndrome and variable phenotype (i.e., severe to modifications, together with the variable clinical features moderate congenital encephalopathy, infantile death or of the patients, make ICF samples an ideal model for psychiatric manifestations) have also been described (Ravn investigating the epigenetic network and their molecular et al. 2003; Moretti and Zoghbi 2006). Mutations in the consequences in several biological pathways (gene tran- X-linked gene encoding methyl-CpG-binding protein 2 scription, DNA replication and recombination, among (MeCP2), including missense, frameshift and nonsense others). mutations and intragenic deletions, account for the condi- tion in up to 96 % of Rett syndrome patients (Amir et al. MeCP2 genetic alterations and Rett syndrome 1999; Moretti and Zoghbi 2006). Interestingly, the increase in MeCP2 dosage due to duplications of the locus and Rett syndrome (MIM #312750) is a progressive neurode- surrounding areas also causes the neurological disorder velopmental disorder characterized by arrested develop- Lubs X-linked mental retardation syndrome (MRXSL, ment between 6 and 18 months of age, regression of MIM #300260) (Van Esch et al. 2005). MeCP2 mutations acquired skills, loss of speech, unusual stereotyped move- in Rett syndrome patients arise in the germline although the ments and intellectual disability (Zachariah and Rastegar phenotypic alterations in the neurological system appear at

123 364 Hum Genet (2013) 132:359–383 early postnatal stages (Zachariah and Rastegar 2012). posttranslational modifications of MeCP2 proteins could Recently, abrogation of MeCP2 function in adult mice has also provide insight into the effect on synaptic plasticity been found to result in severe neurological symptoms mediated by the regulation of specific genes. Recent work commonly observed in Rett syndrome, such as global has shown that phosphorylation of MeCP2 at serine 421 is shrinkage of the brain, increased neuronal cell density, induced by membrane depolarization and leads to the retraction of dendritic arbors, reduction of synaptic proteins regulation of BDNF transcription (Zhou et al. 2006). and altered astrocytic development, among others (Nguyen Interestingly, a mouse model showed that phosphorylation et al. 2012). This is further evidence of the involvement of at serine 421 has widespread effects on synaptic plasticity MeCP2 in regression from a normal mature brain to a Rett- (Li et al. 2011). Neuronal activity also influences dephos- like brain. This dynamism is of vital importance and sug- phorylation of MeCP2 at serine 80, which alters the tran- gests opportunities for reverting the Rett phenotype. In this scription of several genes (Tao et al. 2009). Considering regard, Rett syndrome is not a neurodegenerative disorder, these results together suggests that further research is neurons do not die, opening the opportunities of phenotypic warranted into the role of these MeCP2 posttranslational reversion by means of MeCP2 restoration (Giacometti et al. modifications (and other phosphorylation sites) in neuronal 2007; Guy et al. 2007; Tropea et al. 2009). plasticity. It should be stressed that recent evidence sug- MeCP2 protein is widely expressed in several tissues but gests that MeCP2 is not only involved in transcriptional the highest level of expression has been observed in the regulation, but also possibly in RNA splicing (Young et al. brain (Zachariah and Rastegar 2012). Although a higher 2005), chromatin condensation (similar to H1 function) level of MeCP2 expression has been described in neurons, (Ishibashi et al. 2008) and the silencing of repetitive ele- especially in postmitotic neurons, deregulation of MeCP2 ments (Muotri et al. 2010). These findings demonstrate that expression in glia cells also contributes to the progression MeCP2 function and its involvement in Rett syndrome of Rett syndrome (Ballas et al. 2009). MeCP2 was initially might be more complex than previously appreciated. identified as a transcriptional repressor that binds to Finally, MeCP2 mutations are also linked to a broad methylated CpG dinucleotides and recruits corepressors spectrum of neurological disorders (Van Esch et al. 2005; such as mSin3 and HDACs (Jones et al. 1998). However, in Villard 2007), and to autism (Carney et al. 2003), Angel- recent years, studies have concluded that MeCP2 may act man syndrome (Watson et al. 2001) and Prader–Willi either as a repressor or an activator, depending on its syndrome (Samaco et al. 2004). As mentioned before, interaction proteins (Chahrour et al. 2008; Yasui et al. duplications or triplications on chromosome Xq28 con- 2007). Chahrour et al. (2008) examined the gene expres- taining the MeCp2 region are also associated with the Lubs sion profiles in the hypothalamus of mice lacking or X-linked mental retardation syndrome (Van Esch et al. overexpressing MeCP2 and, contrary to expectation, con- 2005). Taking together, it must be highlighted that both firmed that MeCP2 occupancy preferentially occurs in down- and overexpression of MeCP2 result in altered active genes (85 %) and is associated with binding to the neuron function, an aspect that must be especially con- transcriptional activator CREB1. In accordance with this sidered for therapeutic purposes based on MeCP2 restora- finding, similar genome-wide analyses of MeCP2 binding, tion. Although it is clear that MeCP2 deficiency affects the CpG methylation and gene expression showed that MeCP2 brain function, a definitive molecular pathology of the binds methylated and unmethylated DNA preferentially to MeCP2-associated disorders remains elusive. In this con- actively expressed genes (Yasui et al. 2007). Several cern, progresses are currently being carried out mainly due MeCP2 target genes (UBE3A, DLX5, BDNF and PRODH) to the development of appropriate experimental systems, have been identified (Samaco et al. 2005; Horike et al. such as stem cell-based system allowing the synchronous 2005; Chang et al. 2006; Urdinguio et al. 2008), although differentiation of neuronal progenitors in wild-type or no direct link between MeCP2-dependent expression of mutant MeCP2 (Yazdani et al. 2010) or by the develop- these genes and the phenotypic abnormality of Rett syn- ment of several mouse models that reproduce many traits drome has so far been found. A role for oxidative stress as of Rett syndrome (Na et al. 2012). Hopefully their findings a mechanism underlying the Rett phenotype has been will help us better understand the many facets of the suggested (De Felice et al. 2012) mainly on the basis of pathobiology of the disease. two observations: (i) oxidation of either a single guanine to 8-oxoG or of a single 5mC to 5hmC, significantly inhibits (by at least an order of magnitude) binding of MeCP2 to Genetic alteration of histone modifiers the oligonucleotide duplex (Valinluck et al. 2004); (ii) several MeCP2 target genes affect the oxidative stress The histone modification network is very complex. response, such as BDNF, CREB or Prodh (Chang et al. Post-transcriptional histone modifications can occur in 2006; Urdinguio et al. 2008). Finally, analysis of the various histone proteins (e.g., H2B, H3, H4) and variants 123 Hum Genet (2013) 132:359–383 365

Genetic alterations of epigenetic genes

5mC DNMTs

Ac HATs

Me HMTs Writers P Kinases

DICER 5mC MBDs miRNA/mRNA XPO5 Drosha Pri-mRNA RISC Ac Bromodomains Normal Readers Me Chromodomains miRNA Pre-mRNA development PHD domains PWWP domains Tudor domains

HDAC2 HDAC1 Ac HDACs MeCP2 SINA3 CH3 Me HDMTs Erasers P Phosphatases

PRMT1 CBP CARM1 H4 P300 DNMT3B pCAF SWI/SNF Ac Ac Me PPAc Me Ac Ac Me Epigenetic therapies

…K… DRLVKRHRKAGGKGLGKGGKGRGS -N-terminal HDAC inhibitors 9120 18 16 12 8 5 3 1 HDMT inhibitors DNA demethylating agents Others

Fig. 1 Epigenetic mechanisms disrupted in human disorders. Epige- research. Chemical modifications at histone H4 are shown as a netic mechanisms regulate chromatin function and cell identity. representative example of histone marks. 5-mC; 5-methylcytosine; Ac Appropriate activity of enzymes controlling DNA methylation, histone acetylation, DNMTs DNA methyltransferases, HATs histone histone modifications and non-coding RNAs controls the temporal acetyltransferases, HDACs histone deacetylases, HDMTs histone and spatial patterns of gene expression, DNA repair and DNA demethylases, HMTs histone methyltransferases, MBDs methyl- replication. Their deregulation may contribute to human diseases. binding domain proteins, Me histone methylation, P histone phos- Epigenetic-based therapies, such as histone deacetylase inhibitors, can phorylation, PHD plant homeodomain, PWWP proline–tryptophan– partially alter the phenotype of the disease by recovering the aberrant tryptophan–proline domain, XPO5 exportin-5 epigenetic patterns, and are a promising area in pharmacological (e.g., H3.3) and affect different histone residues (lysine, associated with gene silencing (Bannister and Kouzarides arginine, serine) located in their N-terminal tails (Esteller 2011). Gene transcription is not the only characteristic that 2008; Bannister and Kouzarides 2011). Several chemical is controlled in this way; histone modifications are a groups [methyl, acetyl, phosphate, small ubiquitin-related mechanism for controlling chromatin structure and they modifier (SUMO) and ADP-ribose] may be added in dif- also affect more global biological processes such as DNA ferent degrees depending on the chemical modification repair, DNA replication, alternative splicing and chromo- (mono-, di- or trimethylation) (Bannister and Kouzarides some condensation (Portela and Esteller 2010). 2011). Cross-talk between histone marks can occur within Addition of chemical groups to histone residues is a very the same residue, in the same tail or among different his- dynamic and reversible process catalyzed by two sets of tone tails (Portela and Esteller 2010) and, as a conse- enzymes (and their protein complexes) that have antago- quence, the functional significance of histone modifications nistic activities, enzymes that covalently attach the chem- depends on the combination of all marks (the ‘‘histone ical groups and others for removing them (Fig. 1). code’’). Furthermore, we must not forget that an additional Acetyltransferases (HATs) and histone deacetylases level of complexity exists due to the communication (HDACs) are among the least specific histone modifiers between the epigenetic marks involving DNA, histone and because they are able to modify several residues. Con- chromatin-related proteins. Histone modifications are versely, histone methyltransferases (HMTs), histone involved in gene transcription, although the consequence of demethylases (HDMTs) and kinases have higher specificity each mark depends on the residue affected and the type of (Portela and Esteller 2010). Genetic alterations of histone modification. In general, acetylation of lysines is associated modifier enzymes are frequently linked to human diseases. with transcriptional activation. However, methylation of In this regard, aberrations in the histone modification lysine 4 of the H3 histone is associated with active tran- profiles associated with cancer could be a consequence of scription whereas methylation of lysines 9 and 27 is the genetic disruption of the epigenetic machinery

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(Berdasco and Esteller 2010). Several hematological KAT6B mutations. Their preliminary results suggested that malignancies can be associated with chromosomal trans- the common features are a consequence of haploinsuffi- locations in the coding region of HATs (i.e., CBP-MOZ)or ciency of the C-terminal region, whereas the unique phe- HMTs (i.e., mixed-lineage leukemia 1 (MLL1), or nuclear notypes of GPS could arise from the expression of a receptor binding SET domain protein 1 (NSD1). In solid truncated protein that acquires new cellular functions tumors, both HMT genes [such as EZH2, mixed-lineage (Campeau et al. 2012b). leukemia 2 (MLL2)] and DNMTs [i.e., Jumonji domain- The molecular mechanisms of abrogation of KAT6B containing protein 2C (JMJD2C/GASC1)] are known to be function that lead to defective neural development are amplified (Berdasco and Esteller 2010). In this section we not currently known. The Querkopf mouse model that will focus on non-tumoral human diseases in which the only expressed a 5 % of the MYST4 levels quantified for epigenetic profile changes as a consequence of genetic wild-type mice leads to a phenotype commonly observed alterations in histone modifiers (Table 1). in human syndromes: brain development defects, facial dysmorphisms and alteration of bone growth (Thomas MYST4 acetyltransferase (KAT6B) mutations et al. 2000), supporting the role of KAT6B in cerebral in Genitopatellar syndrome and Say-Barber-Biesecker- cortex development. According to this idea, KAT6B is Young-Simpson syndrome expressed in developing cerebral cortex, adult neural stem cells, osteoblasts and germ cells (Merson et al. Genitopatellar syndrome (GPS, MIM #606170) is a rare 2006). A study performed in one Noonan-like phenotype skeletal dysplasia consisting of microcephaly, severe psy- patient, with a chromosomal breakpoint in KAT6B chomotor retardation and craniofacial defects, associated resulting in 50 % gene expression, and in Querkopf mice, with congenital flexion contractures of the lower extremi- described a reduction of H3 acetylation that specifically ties, abnormal or missing patellae, and urogenital anoma- dysregulates the expression of genes in the MAPK lies (Reardon 2002). To date it has been described in only pathway (Kraft et al. 2011). 18 subjects (Campeau et al. 2012a). Whole-exome sequencing identified mutations in the KAT6B acetyl- Genetic disruption of ep300/CBP acetyltransferases transferase that lead to protein truncation (Campeau et al. in Rubinstein–Taybi syndrome 2012a; Simpson et al. 2012). All mutations are heterozy- gous, exhibit autosomal dominant inheritance and occur in The Rubinstein–Taybi syndrome (RSTS, MIM #180849) is the proximal portion of the last exon (Campeau et al. a well-defined disease characterized by postnatal growth 2012a). KAT6B is a member of the MYST family of deficiency, microcephaly, specific facial characteristics, proteins containing a conserved acetyltransferase domain broad thumbs, big toes and intellectual disability. An (Champagne et al. 1999). The absence of decreased increased risk of tumors (mainly leukemia in childhood and expression of the KAT6B transcript has been described in meningioma in adulthood) has been observed (Hennekam GPS patients (Campeau et al. 2012a); however, GPS sub- 2006). Although the exact molecular etiology of RSTS is jects were characterized by decreased global acetylation of not clearly understood, it is widely accepted that RSTS is histone H3 and H4 (Simpson et al. 2012). associated with breakpoints, translocations, mutations and Heterozygous mutations of KAT6B have also been microdeletions of chromosome 16p13.3 (Lacombe et al. described in patients with Say-Barber-Biesecker-Young- 1992). Petrij et al. (1995) were the first to report that Simpson syndrome (SBBYS, MIM #603736) (Clayton- mutations in the gene encoding the CREB binding protein Smith et al. 2011). The main clinical features associated (CBP), located in the aforementioned region, could cause with the syndrome are distinctive facial appearance, severe RSTS. Recent investigations employing larger series of hypotonia and feeding problems, associated skeletal prob- RSTS samples detected CBP mutations in 45–55 % of lems, cardiac defects, severe intellectual disability, delayed patients (Roelfsema et al. 2005; Tsai et al. 2011). motor milestones, and significantly impaired speech Furthermore, CBP has a homolog located at 22q13.2, (Clayton-Smith et al. 2011). Unlike with GPS syndrome, known as the E1A-binding protein p300 (p300) (Arany mutations in SBBYS patients are located throughout the et al. 1994). The exact frequency of genetic alterations of gene or more distally in the last exon. Although GPS and p300 in RTS is not yet known, but some sources estimate it SBBYS share several clinical features, such as severe to be 3 % (Bartholdi et al. 2007; Bartsch et al. 2010). Since intellectual disability, cardiac defects and genital abnor- a cytogenetic or molecular abnormality in p300/CBP could malities, the range of phenotypic alteration varies between be detected in about 55 % of patients, further work to the two syndromes (Campeau et al. 2012b). Campeau and explain the cause of the syndrome in the remaining 45 % of collaborators created a database for establishing correla- patients without a ‘‘classic’’ genetic abnormality is still tions between phenotype and genotype in patients carrying needed. 123 Hum Genet (2013) 132:359–383 367

CREB binding protein was first identified as a nuclear spectrum of clinical features, such as intellectual disabilities, transcription coactivator that binds specifically to CREB developmental delays, sleep disturbance, craniofacial and when it is phosphorylated (Chrivia et al. 1993), while p300 skeletal abnormalities (including brachydactyly type E), was originally described by protein-interaction assays with cardiac defects and autism (Aldred et al. 2004). Hetero- the adenoviral E1A oncoprotein (Eckner et al. 1994). zygous mutations in the HDAC4 deacetylase gene located Although both proteins are highly homologous (63 % on chromosome 2q37.2 have been reported in BMRS homology at the amino acid level) and have common subjects (Williams et al. 2010; Morris et al. 2012). HDAC4 interaction partners, they have distinct cellular functions acts as a corepressor for transcription factors regulating the and cannot always replace one another (Viosca et al. 2010). expression of genes from the osteogenic, chondrogenic, There are two biological mechanisms whereby defects in myogenic and neurogenic differentiation pathways (Miska p300/CBP function could cause the RTS symptoms: et al. 2001; Arnold et al. 2007; Chen and Cepko 2009). (i) CBP and p300 proteins act as cofactors for over 300 HDAC4 is essential for the repression of RUNX2 and transcriptional factors, including several regulators MEF2 transcription factors in normal bone development involved in neuronal activity, such as c-Fos, c-Jun, CREB (Arnold et al. 2007). Indeed, mice with a deleted MEFC2 or NF-jß, known oncoproteins (myb), transforming viral gene have impaired chondrogenic and osteogenic devel- proteins (E1A, E6, large T antigen) and tumor-suppressor opment that antagonizes the phenotype of the Hdac4 proteins (p53, E2F, RB, Smads, RUNX, BRCA1) (Chan mutant mice, which is similar to the human BDMR phe- and La Thangue 2001; Kasper et al. 2011); (ii) both pro- notype (Arnold et al. 2007; Rajan et al. 2009). These teins have HAT activity that targets the N-terminal tails of results suggest that haploinsufficiency of HDAC4 causes histones and contributes to transcriptional activation by BDMR through its ability to regulate important master relaxing the structure of the nucleosomes (Ogryzko et al. genes of cellular differentiation. 1996). CBP and ep300 have some common activities, such as the acetylation of H4K5, H3K14, H3K18, H3K27 and Mutations in histone methyltransferase EHMT1 H3K56 (Das et al. 2009; Jin et al. 2011). However, they in Kleefstra syndrome also have unique properties such as substrate specificity profiles that could explain functional differences of both Kleefstra syndrome (MIM #610253), previously known as enzymes (McManus and Hendzel 2003). RSTS disorder 9q subtelomeric deletion syndrome, is characterized has been modeled in mice, and several heterozygous by severe intellectual disability, hypotonia, brachy(micro) cbp ± mice (homozygous cbp -/- mutants are embryonic cephaly, epileptic seizures, flat face with hypertelorism, lethal) have been generated (Bourtchouladze et al. 2003; synophrys, anteverted nares, everted lower lip, carp mouth Alarcon et al. 2004). These model animals exhibit deficits with macroglossia, and heart defects (Willemsen et al. in long-term memory and cognitive impairments reminis- 2012). The mutational landscape of Kleefstra patients cent of human RSTS neural symptoms, confirming the role includes a microdeletion in the distal long arm of chro- of CBP in the etiology of the disease (Alarcon et al. 2004; mosome 9q or intragenic loss of function mutations in the Korzus et al. 2004). At the molecular level, these mice histone methyltransferase EHMT1 (Kleefstra et al. 2006, have reduced HAT activity, decreased acetylation of spe- 2009), both leading to haploinsufficiency of EHMT1. cific histone proteins and impaired CBP-dependent gene EHMT1 is a specific HMT for lysine 9 at histone H3 and is expression (Alarcon et al. 2004; Korzus et al. 2004). The involved in gene repression (i.e., the NF-kB gene) (Ogawa role of CBP in neural differentiation and development has et al. 2002; Ea et al. 2012). It has not been established how been recently demonstrated in CBP genetically modified EHMT1 disruption results in the phenotypic skills of models (Wang et al. 2010). Phosphorylation of CBP by Kleefstra syndrome, but recent research on EHMT mutants atypical protein kinase C f is necessary for CBP binding to in Drosophila melanogaster demonstrates that learning and neural promoters, followed by histone acetylation and memory defects could be restored after re-expression of transcriptional activation, leading to neural differentiation EHMT (Kramer et al. 2011). Interestingly, the same of stem cell precursors (Wang et al. 2010). This mechanism authors have recently identified new genetic mutations could explain how CBP alterations can result in cognitive affecting epigenetic modifiers in Kleefstra syndrome sub- dysfunction of RSTS patients. jects without mutations in the EHMT1 gene, including the methyl-binding domain MBD5, the histone methyltrans- HDAC4 histone deacetylase mutations ferase MLL3 or the chromatin-remodeling factor in Brachydactyly-mental retardation syndrome SMARCB1 (Kleefstra et al. 2012). These findings highlight the crucial role of epigenetic modifiers in brain develop- Brachydactyly-mental retardation syndrome (BDMR, MIM ment and strongly emphasize the need to explore this area #600430) is a complex disease that presents a wide of research further. 123 368 Hum Genet (2013) 132:359–383

NSD1 histone methyltransferase genetic alterations have an increased risk of developing malignancy before in Sotos syndrome adulthood, including neuroblastoma, Wilms tumors and hematological malignancies (Rahman 2005). NSD1 also Sotos syndrome (MIM #117550) is an autosomal dominant has a tumor-suppressor function (Berdasco et al. 2009). condition characterized by overgrowth that results in tall NSD1 function is abrogated in neuroblastoma and glioma stature and macrocephaly, a distinctive facial appearance, cells by transcriptional silencing associated with CpG learning disability (Lapunzina 2005; Tatton-Brown and island-promoter hypermethylation, and restoration of its Rahman 2007), and an increased incidence of malignant expression demonstrates that its tumor-suppressor features neoplasms (Rahman 2005). The distinctive head shape and are mediated by a mechanism dependent on MEIS1 size has led to Sotos syndrome sometimes being called expression (Berdasco et al. 2009). cerebral gigantism (Tatton-Brown and Rahman 2007). Finally, occasional individuals have NSD1 defects that Most cases of NSD1 mutational mechanisms, including overlap clinically with Sotos syndrome and other condi- truncating, missense and splice-site mutations and tions, such as Weaver syndrome 1 (WVS1, MIM #277590) deletions, result in loss of function of the NSD1 protein (Douglas et al. 2003). Beckwith–Wiedemann syndrome (Tatton-Brown and Rahman 2007). Mutations in the (BWS, MIM #130650) is, like Sotos syndrome, an over- nuclear receptor SET domain containing protein-1 gene growth syndrome. It is cause by deregulation of imprinted (NSD1), which encodes a histone methyltransferase of growth-regulatory genes within the 11p15 region. Inter- lysine residues H3K36 and H4-K20, are found in patients estingly, correlations between the two syndromes have exhibiting the clinical symptoms of Sotos syndrome been found: first, unexplained Beckwith–Wiedemann (Kurotaki et al. 2002; Rayasam et al. 2003). Recently, patients could be related to NSD1 deletions or mutations mutations in the NFIX gene were associated with a Sotos (2/52 cases) and secondly, 11p15 anomalies (including the syndrome-like phenotype without NSD1 mutations (Yon- KCNQ10T1 imprinting center) were identified in Sotos eda et al. 2012). syndrome cases (2/52) (Baujat et al. 2004; Mayo et al. NSD1 is essential for early postimplantation of embryos 2012). A potential role for NSD1 in imprinting of the and NSD1 homozygous mutants are embryonic lethal, 11p15 region is suggested, although the molecular basis for although heterozygous mutant NSD1 are viable and fertile this association is not known. (Rayasam et al. 2003). The NSD1 protein contains a su(var)3-9, enhancer-of-zeste, trithorax (SET) domain EZH2 histone methyltransferase mutations responsible for HMT activity and other functional domains, and Weaver syndrome including plant homeodomain (PHD) and proline–trypto- phan–tryptophan–proline (PWWP) domains, both of which Weaver syndrome 2 (WVS2, MIM #614421) is an over- are involved in a protein–protein interaction (Kurotaki growth syndrome characterized by tall stature, advanced et al. 2001). Additionally, the potential of NSD1 to mono- bone age, macrocephaly, hypertelorism, learning disabili- and dimethylate lysines K218 and K221 of the p65 subunit ties and dysmorphic facial features (Weaver et al. 1974). A of the immune response gene NF-kB has been noted (Lu predisposition to hematological malignancies has also been et al. 2010). NSD1 has previously been shown to interact reported (Basel-Vanagaite 2010). Heterozygous mutations with nuclear receptors, such as Nizp1, a DNA-binding in the histone methyltransferase EZH2 gene on chromo- transcriptional repressor (Huang et al. 1998; Nielsen et al. some 7q36.1 have been identified in Weaver syndrome 2004), but to date there has been no evidence clarifying patients (Gibson et al. 2012). EZH2 protein is a member of whether NSD1 mutations contribute to deregulation of the polycomb repressive complex 2 (PRC2), together with brain function. It has become clear that NSD1 is a versatile SUZ12 and EED, which catalyses the trimethylation of protein that can act as a corepressor or coactivator, lysine H3K27 (Kirmizis et al. 2004). Mammalian EZH2 depending on the cellular context (Huang et al. 1998; has critical roles in X-chromosome inactivations, genomic Pasillas et al. 2011). According to this idea, binding of imprinting during germline development, stem cell main- NSD1 PHD domains to target genes is guided by the tenance and cell lineage determination, including osteo- presence of specific histone marks of promoters (Pasillas genesis, myogenesis and hematogenesis (Chou et al. 2011; et al. 2011), specifically methylation at lysine H3K4 and Wyngaarden et al. 2011). A role for EZH2 in regulating the H3K9. By binding to trimethylated H3K9, NSD1 can circadian-clock functions has been suggested (Etchegaray recognize genes that are transcriptionally repressed and et al. 2006). In addition, mice with targeted mutant EZH2 interact with other repression complexes (i.e., DNMT1 or beta cells have reduced beta cell proliferation and beta cell HP1), whereas its interaction with trimethylated H3K4 mass (Chen et al. 2009), whereas mice with EZH2 mutant allows binding to active genes (Pasillas et al. 2011). In satellite cells exhibit defects in muscle regeneration (Juan addition, patients with genetic disruption of the NSD1 gene et al. 2011). Some characteristics of these phenotypes are 123 Hum Genet (2013) 132:359–383 369 shared with that of human Weaver syndrome, such as gene located on the Xp11 chromosome have been identi- defects in limb development (Wyngaarden et al. 2011). fied in subjects with MRXSSD (Laumonnier et al. 2005; However, to date, few studies have provided any insight into Abidi et al. 2007; Koivisto et al. 2007). The PHF8 protein the specific contribution of EZH2 mutations in the Weaver contains a PHD-type domain zinc finger domain and a phenotype. As described above, some patients with Weaver Jumanji domain, the latter conferring histone demethylat- syndrome have a mutated NSD1 gene that is responsible for ing catalytic activity with specificity for: mono- and the overgrowth Sotos syndrome (Douglas et al. 2003). There dimethylated histone H3 at lysine K9 (Yu et al. 2010) and are some clinical features common to both syndromes (i.e., mono-methyl histone H4 at lysine K20 (Qi et al. 2010). developmental delay, overgrowth and macrocephaly), but PHF8 transcript is strongly expressed in the embryonic and some features are specific to Weaver syndrome 2 (i.e., ret- early postnatal steps of brain development (Laumonnier rognathia with a prominent chin crease or carpal bone age) et al. 2005), implying a connection between PHF8 muta- (Gibson et al. 2012). Indeed, EZH2 protein acts in the PI3K/ tions and the MRXSSD phenotype. Some evidences of the mTOR pathway, which has been associated with growth functional role of PHF8 in different experimental models defects. This suggests that the pathways through NSD1 and exist (Liu et al. 2010; Qi et al. 2010). In zebrafish, it has EZH2 HTMs that contribute to overgrowth disorders can be been described that PHF8 regulates brain apoptosis and different (Tatton-Brown et al. 2011). craniofacial development through the transcriptional gene regulation (Qi et al. 2010); in Caenorhabditis elegans, a Histone methyltransferase (MLL2) and demethylase RNA interference-based functional genomic project iden- (JMJD3) mutations in Kabuki syndrome tified PHF8 as a gene involved in controlling cellular growth and differentiation during embyogenesis (Fernan- Kabuki syndrome 1 (MIM #147920) is an autosomal dez et al. 2005); in human HeLa cells, PHF8 deficiency by dominant intellectual disability syndrome with additional siRNA mechanisms leads to a delay in G1/S transition and features, including a highly distinctive recognizable facial its dissociation from chromatin in early mitosis which phenotype characterized by long palpebral fissures with demonstrates an active role of PHF8 in the control of cell eversion of the lateral third of the lower eyelids, a broad cycle (Liu et al. 2010). Interestingly, PHF8 interacts with and depressed nasal tip, large prominent earlobes, scoliosis, another MRXSSD protein, the transcription factor ZNF711 short fifth finger, persistence of fingerpads, radiographic (Kleine-Kohlbrecher et al. 2010). PHF8 and ZNF11 pro- abnormalities of the vertebrae, hands, and hip joints, and teins share a set of target genes, being of special relevance others (Niikawa et al. 1981). Mutations in the histone the interaction of both proteins with JARID1C (KDM5C) methyltransferase MLL2 gene are a major cause of Kabuki (also involved in alterations of the intelectual ability) syndrome (type 1) (Ng et al. 2010; Hannibal et al. 2011), (Kleine-Kohlbrecher et al. 2010; Claes et al. 2000). In but mutations in the histone demethylase KDM6A have addition to MRXSSD syndrome, defects affecting the also been found in Kabuki syndrome (type 2, MIM chromosomal region of PHF8 (a larger Xp11.22 deletion #300867) (Lederer et al. 2012). MLL2 is a lysine H3K4- that includes the FAM120C and WNK3 genes) have also specific histone methyltransferase that belongs to the SET1 been associated with autism (Qiao et al. 2008). family of proteins (Dillon et al. 2005), whereas KDM6A (JMJD3) is a histone demethylase that specifically acts in Histone demethylase JARID1C (KDM5C) mutations mono- di- and trimethylated lysine H3K27 (Hong et al. in Claes-Jensen X-linked mental retardation syndrome 2007; Lan et al. 2007). Both enzymes help regulate genes from the myogenic lineage during embryogenesis (Aziz Mutations in the histone demethylase JARID1C (KDM5C) et al. 2010; Seenundun et al. 2010). The identification of were first identified in individuals with X-linked mental mutations in MLL2 and KDM6A suggests a crucial effect retardation syndrome with additional features of progres- of altered histone methylation profiles on the phenotype of sive spastic paraplegia, facial hypotonia, aggressive Kabuki syndrome. behavior and strabismus (MIM #300534) (Claes et al. 2000; Jensen et al. 2005). Heterogeneous clinical features Histone demethylase PHF8 mutations in Siderius associated with XLMR and mutated KDM5C have been X-linked mental retardation syndrome consistently identified since then (Abidi et al. 2008; Santos- Rebouc¸as et al. 2011; Ounap et al. 2012). KDM5C gene Siderius X-linked mental retardation syndrome (MRXSSD, encodes a specific histone H3 demethylase at lysine K4 MIM #300263) is an inherited condition that was first (Tahiliani et al. 2007). It is ubiquitously expressed described in 1999 as a heterogeneous intellectual disability although fetal brain tissues have higher KDM5C expres- syndrome associated with cleft lip/cleft palate (Siderius sion levels than other tissues (Xu et al. 2008). The tran- et al. 1999). Mutations in the PHD finger protein 8 (PHF8) scriptional repressor activity of KDM5C is mediated by the 123 370 Hum Genet (2013) 132:359–383

Re-1 silencing transcription factor (REST) complex as Mi-2/nuRD, contain HDAC and MBD proteins in the (Tahiliani et al. 2007). Interestingly, knock-out of the same complex (Murawska and Brehm 2011). The INO80 KDM5C complex results in increased trimethylation at subfamily is the most recently identified SWI/SNF family H3K4 and gain of expression of SCN2A and SYN1 neuro- of chromatin remodelers. Mammalian INO80 complex logical genes, and provides evidence of the contribution of comprises the INO80 catalytic unit and Snf2-related CBP KDM5C complex to X-linked mental retardation defects activator protein (SRCAP) and p400 subunits (Morrison (Tahiliani et al. 2007). and Shen 2009). The INO80 subfamily is the most evolu- tionarily conserved of all the chromatin-remodeling com- plexes due to the high degree of homology of its ATPase Mutations in chromatin remodelers subunit (Morrison and Shen 2009). Apart from regulation of transcription, the INO80 complex is involved in genome Nucleosome positioning and, consequently, DNA accessi- stability pathways, such as DNA repair, replication, telo- bility may be controlled by mechanisms that are indepen- mere regulation and centromere stability (Ho and Crabtree dent of histone-modifying enzymes. Several groups of 2010). In summary, ATP-dependent enzymes that remodel protein complexes (‘‘chromatin-remodeling complexes’’) chromatin are important regulators of chromatin dyna- are known to restructure nucleosomes in an ATP hydro- mism. Evidence is emerging that alterations in such chro- lysis-dependent manner. To date, four families of chro- matin-remodeling complexes have consequences for matin remodelers have been described in eukaryotes: SWI/ normal development. Some examples of genetic mutations SNF, ISWI, NURD/Mi-2/CHD, and INO80/SWR1 (Har- of chromatin-remodeling complexes in human diseases are greaves and Crabtree 2011). The ATPase domain is a summarized in this section (Table 1). common feature, but the composition of the different subunits comprising the complex is highly variable. In a ATXN7 mutation in Spinocerebellar Ataxia 7 similar manner, each ATPase domain may be targeted to specific domains (i.e., bromodomain, DNA helicase, etc.). Spinocerebellar Ataxia Type 7 (SCA7; MIM 164500) is an Together, the binding affinity and the complex composition autosomal dominant inherited neurodegenerative disorder confer unique features on chromatin remodelers in a wide characterized by progressive cerebellar ataxia, including range of biological processes and genomic contexts. dysarthria and dysphagia, and cone-rod and retinal dys- SWI/SNF is one of the best studied chromatin-remod- trophy with progressive central visual loss resulting in eling complexes in human cells and is composed of at least blindness in affected adults. The disease is caused by an 15–20 subunits, including ATPases, catalytic subunits (i.e., expanded CAG trinucleotide repeat encoding a polygluta- SMARCA2 and SMARCA4) and structural components mine tract in ataxin-7 (ATXN7) gene, from 4 to 35 repeats involved in target recognition or stabilization functions in normal gene to a variable expansion of 36–306 repeats in (i.e., ARID1A, ARID1B and SMARCC1) (Hargreaves and pathogenic ATXN7 variants (Garden and La Spada 2008). Crabtree 2011). All members of this complex contain either ATXN7 protein is a transcription factor with important SMARCA2 (also known as Brahma protein) or SMARCA4 roles in chromatin regulation through its effect on histone (also known as BRG1) as a catalytic unit. The two proteins modification and histone deubiquitination. It is a member share 75 % amino acid homology (Santen et al. 2012). The of the transcription coactivator complex STAGA (SPT3/ SWI/SNF complex plays a crucial role in cell differentia- TAF9/GCN5) with acetyltransferase activity, but may also tion (Ho et al. 2009), cell cycle (Nagl et al. 2007) and DNA be found in the USP22 deubiquitination complex (Sopher repair (Park et al. 2006). In the human ISWI (imitation et al. 2011). Although the nuclear expression of ATXN7 is switch) family of chromatin remodelers, the catalytic sub- necessary for transcriptional regulation, a functional role unit is represented by SNF2H and SNF2L proteins (Flaus for cytoplasmic ATXN7 in the regulation of cytoskeletal and Owen-Hughes 2011). ISWI complexes participate in dynamics (mediated by its interaction with microtubules) biological functions such as chromatin assembly, nucleo- has recently been proposed (Nakamura et al. 2012). some spacing, DNA replication and activation or repres- Defects of the nuclear ATXN7 gene have been correlated sion of transcriptional regulation (Erdel and Rippe 2011). with the SCA7 phenotype (Chen et al. 2012a, b), although The CHD family also contains a SNF2L ATPase domain the molecular mechanisms underlying the disease are not together with tandem chromodomains in the N-terminal clearly understood and the effect of epigenetic dysregula- region (Murawska and Brehm 2011). CHD complexes are tion of target genes is still a matter of debate. Some results highly versatile and although they are involved in tran- from yeast and mice indicate that loss of the Gcn5 ace- scriptional regulation, various CHD regulatory complexes tyltransferase function triggered by polyQ-Atxn7, resulting are involved in the initiation, elongation or termination of in chromatin structure changes, could be involved in the transcription. Furthermore, specific CHD complexes, such SCA7 phenotype (Yoo et al. 2003; McMahon et al. 2005; 123 Hum Genet (2013) 132:359–383 371

Helmlinger et al. 2006). In contrast, loss of Gcn5 functions repeats (Gibbons et al. 2000). The interplay between in mice bearing polyQ-Atxn7 accelerates neuronal dys- ATRX and the DNA methylation machinery is reinforced function in a mechanism that is independent of gene by the discovery that the methyl-binding domain protein expression changes (Chen et al. 2012a, b). Deciphering the MECP2 targeted the C-terminal helicase domain of ATRX exact causal consequences of ATXN7 dysregulation in to heterochromatic foci (Nan et al. 2007). MeCP2 is also SCA7 disease through its role as nuclear transcription mutated in Rett syndrome, so the finding suggests that regulator or cytoplasmic function will need further alteration of the MECP2–ATRX interaction leads to path- research. ological changes that contribute to the intellectual dis- ability phenotype observed in both syndromes. ATRX mutations in alpha-thalassemia X-linked mental retardation syndrome Mutations in ERCC6 and Cockayne syndrome

ATR-X syndrome (MIM #301040) is an X-linked disorder Cockayne syndrome types A (CSA; MIM #216400) and B comprising severe psychomotor retardation, characteristic (CSB; MIM #133540) are autosomal recessive disorders facial features, genital abnormalities, and the blood disease caused by mutation in the ERCC8 and ERCC6 genes, alpha-thalassemia (Gibbons et al. 1995). Mutations in the respectively (Henning et al. 1995; Laugel et al. 2010). ATRX gene located at Xq21.1 and coding for a member of Approximately 62 % patients diagnosed with Cockayne the SWI/SNF chromatin-remodeling family of proteins syndrome carry mutations of the ERCC6 gene (Laugel underpin the molecular genetics of the disease (Gibbons et al. 2010). The syndromes are characterized by severe et al. 1995). The X-linked mental retardation-hypotonic postnatal growth failure, progressive neurological dys- facies syndrome (MIM #309580) and the alpha-thalassemia function and traits reminiscent of normal aging, such as myelodysplasia syndrome (MIM #300448) are also asso- visual impairment and sensorineural hearing loss and loss ciated with mutations in the ATRX gene (Abidi et al. 2005; of adipose tissue (Licht et al. 2003). ERCC (excision Gibbons et al. 2003). The N-terminus contains a globular repair cross-complementing) genes are part of the nucle- domain, called ADD (ATRX-DNMT3-DNMT3L) that can otide excision repair (NER) pathway, which are respon- bind to the N-terminal of histone H3 (Argentaro et al. sible for removing DNA lesions such as UV-induced 2007). Indeed, ATRX is known to be required for the DNA damage. ERCC6 is a nuclear protein containing a incorporation of the histone H3.3 specifically at telomeric SWI/SNF-like ATPase domain, a nucleotide-binding sequences (Lewis et al. 2010). On the other hand, the domain and an ubiquitin-binding domain (Anindya et al. C-terminus contains seven helicase/ATPase domains that 2010). Apart from NER functions, ERCC6 is also share sequence homology with the SNF2 family of proteins involved in transcription regulation, chromatin mainte- (Picketts et al. 1996). Through this domain, ATRX shows nance and remodeling (Newman et al. 2006). At the in vitro ATP-dependent nucleosome remodeling and DNA transcriptional level, CSB cooperates with the NurD/ translocase activities (Gibbons et al. 2003). The ATRX CHD4 complex for controlling transcription of rRNA protein is expressed genome-wide, but is enriched at telo- genes (Xie et al. 2012). In this regard, CHD4/NuRD is meric and subtelomeric regions (Law et al. 2010). In this involved in maintaining silenced rRNA genes but in context, decreased ATRX expression is associated with permissive contexts (‘‘poised’’ for transcription), whereas altered expression of telomere-associated RNA (Goldberg CSB mediates the transition from the permissive to the et al. 2010) and the DNA-damage response during S-phase active state (Xie et al. 2012). CSB-mediated activation at telomeric regions of pluripotent stem cells (Wong et al. could be due, at least in part, in conjunction with the 2010). The mechanisms by which ATRX is recruited to CSB–G9a interaction, to an increase in trimethylated telomeric regions are not fully understood, although ATRX K9H3 and recruitment of Pol-I to chromatin (Yuan et al. binding depends on trimethylation at K9H3 (Kourmouli 2007). A new chromatin connection for CSB has recently et al. 2005). It binds to tandem repeat sequences with been proposed (Batenburg et al. 2012). Primary fibro- G-rich motifs and has been predicted to form non-B DNA blasts derived from a CSB patient had a dysfunctional structures (Law et al. 2010). More importantly, the size of telomere structure (Batenburg et al. 2012). CSB knock- the tandem repeats located in specific genes influences their down was accomplished with alterations in TERRA, a expression (Law et al. 2010), providing a molecular large non-coding telomere repeat-containing RNA, explanation of how the same mutation at the ATRX gene resulting in alterations of telomere length and integrity can result in different phenotypes. Furthermore, ATRX (Batenburg et al. 2012). Finally, a role for CSB in con- mutations have been correlated with alterations in the DNA trolling key mitochondrial functions in addition to the methylation patterns of highly repeated sequences, nucleolus function has been proposed (Berquist et al. including rDNA, Y-specific satellite and subtelomeric 2012). 123 372 Hum Genet (2013) 132:359–383

SRCAP mutations and Floating-Harbor syndrome promotion of the formation of multipotent migratory neural crest that gives rise to craniofacial bones and cartilages, Floating-Harbor syndrome (FHS; MIM #136140) is a rare and the peripheral nervous system, amongst others (Bajpai condition characterized by proportionate short stature, et al. 2010). Recent in vitro studies have suggested that delayed osseous maturation, language deficits and a typical CHD7 may directly regulate BMP4 expression, a protein facial appearance. Mutations in the SNF2-related CBP involved in cartilage and bone formation, by binding with activator protein (SRCAP) cause the FHS syndrome (Hood an enhancer element downstream of the BMP4 locus (Jiang et al. 2012). SRCAP expression has also been linked to et al. 2012). More CHD7 targets have been identified, such cancer, whereby it positively modulates PSA antigen as the CHD7-dependent regulation (in association with expression and promotes proliferation in prostate cancer BRG1) of SOX9 and TEIST1 genes in human neural crest cells (Slupianek et al. 2010) and potentiates Notch- cells (Bajpai et al. 2010). Mechanisms in which CHD7 dependent gene activation (Eissenberg et al. 2005). With regulates downstream genes vary in a tissue- and cell- regard to its molecular activity, SCARP catalyzes in vitro specific manner and depend on specific binding to meth- incorporation of the histone variant H2A.Z into chromatin ylated histone H3 lysine 4 in enhancer regions (Schnetz (Ruhl et al. 2006), a histone with a well-known function in et al. 2009). Although further research is needed, all these transcription regulation and cell-cycle progression. As an findings suggest that mutations in CHD7 could transcrip- example, SRCAP expression in yeast is important for the tionally deregulate tissue-specific genes and developmental deposition of such histone variants in specific promoters genes resulting in the CHARGE phenotype. like SP-1, G3BP and FAD synthetase (Wong et al. 2007). Interestingly, the demethylation effect after 5-Aza-20- Mutations in SWI/SNF complex family genes deoxycytidine treatment, a drug approved by the US Food in Coffin-Siris syndrome and mental retardation and Drug Administration (FDA) for the treatment of hematological malignancies, requires the activity of Coffin-Siris syndrome (CSS, MIM #135900) or ‘‘fifth SCARP to introduce H2A.Z, which facilitates the acqui- digit’’ syndrome is a multiple congenital anomaly-mental sition of nucleosome-free regions (Yang et al. 2012). On retardation syndrome characterized by severe develop- the other hand, SRCAP is also an interaction partner of the mental delay, coarse facial features, hirsutism and absent histone acetyltransferase CBP, meaning that SRCAP-CBP fifth fingernails, toenails and distal phalanges (Santen et al. colocalization may occur at transcriptionally active sites 2012). In a recent study, 87 % of patients with CSS carried (Monroy et al. 2001). a mutation in one or more members of the SWI/SNF family of genes, which includes SMARCB1, SMARCA4, SMAR- CHD7 mutations and CHARGE syndrome CA2, SMARCE1, ARID1A and ARID1B (Santen et al. 2012; Tsurusaki et al. 2012). Interestingly, CSS patients carrying The acronym CHARGE (MIM # 214800) stands for colo- different genetic mutations of the SWI/SNF chromatin- boma of the eye, heart anomaly, choanal atresia, retarda- remodeling factors gave rise to similar CSS phenotypes tion of mental and somatic development, genital and/or (Tsurusaki et al. 2012), suggesting a general role for these urinary abnormalities and ear abnormalities and/or deaf- complexes in coordinating chromatin conformation and ness (Sanlaville et al. 2006). It is an autosomal dominant gene expression. Deregulation of the SWI/SNF complexes condition with genotypic heterogeneity, although most is also a common feature of tumorigenesis through its cases are due to the mutation or deletion of the chromod- function in mammalian differentiation, proliferation and omain helicase DNA-binding domain protein-7 (CHD7), a DNA repair (Reisman et al. 2009). However, the link member of SNF2-like ATP-dependent chromatin-remod- between SWI/SNF mutations and intellectual disorders is eling enzymes (Sanlaville et al. 2006). CHD7 mutations still unclear. SMARCA2 and SMARCA4 are catalytic have been also identified in Kallmann syndrome, a devel- subunits with ATPase activity, while ARID1A and opmental disorder that shares with CHARGE some phe- ARID1B are structural subunits involved in target recog- notypic features such as impaired olfaction and nition and protein–protein interactions (Hargreaves and hypogonadism (Kim et al. 2008). Mice with heterozygous Crabtree 2011). Both types of subunit are necessary to mutations in CHD7 are a good model for studying regulate the transcription of several genes, such as c-FOS, CHARGE syndrome, and analyses of mouse mutant phe- vimentin, CD44, cyclins, E-cadherin and important tran- notypes have demonstrated a role in the development and scription factors that have been functionally linked to SWI/ function of the neuronal system. CHD7 is necessary for SNF (Reisman et al. 2009; Santen et al. 2012). mammalian olfactory tissue development and function Mutations in SMARCA2 have also been described in (Layman et al. 2009), proliferation of inner ear neuroblasts patients with the Nicolaides–Baraitser syndrome (NBS, and inner ear morphogenesis in mice (Hurd et al. 2010), MIM # 601358), which is characterized by severe 123 Hum Genet (2013) 132:359–383 373 intellectual disability, early-onset seizures, short stature, is an autosomal dominant neurodegenerative disorder dysmorphic facial features and sparse hair (Van Houdt characterized by death of the motor neurons in the brain, et al. 2012; Wolff et al. 2012). Interestingly, Harikrishnan brainstem and spinal cord, resulting in fatal paralysis and et al. (2005) found that SMARCA2 associates with MECP2 respiratory failure with a typical disease course of and regulates FMR1 gene repression in mouse fibroblasts 1–5 years. Heterozygous mutations in the TAR DNA- and human T-lymphoblastic leukemia cells. Methylation at binding protein 43 (TARDBP) on chromosome 1p36, promoter sites specified the recruitment of MECP2/ encoding for the TDP43 protein, are present in a 50 % of SMARCA2; while inhibition of methylation was associated individuals affected by ALS10 (Ling et al. 2010). TARD- with complex release (Harikrishnan et al. 2005). These BP is a member of the miRNA machinery. It has a double results highlight an interesting link between epigenetic effect on miRNA pathway. First, it enhances precursor marks and ATPase-dependent chromatin remodeling. How miRNA (pre-miRNA) production by both interacting with SWI/SNF deregulation produces altered expression pat- the nuclear complex of Drosha or by direct binding to the terns of genes associated with the CSS or NBS phenotype primary miRNAs (pri-miRNAs) in the nucleus; and sec- is not clear, although some clues about the role of the ondly, it binds to the terminal loops of pre-miRNAs in the complex in neural differentiations could help interpret cytoplasm by interaction with the Dicer complex (Kawa- some features (Seo et al. 2005; Lessard et al. 2007). hara and Mieda-Sato 2012). Under non-pathological con- ditions, TARDBP is mainly localized inside the nucleus, but altered cellular distributions, including neuronal cyto- Mutations in non-coding RNA machinery plasmic, intranuclear inclusions and dystrophic neurites or glial cytoplasmic locations are found in ALS10 and FTLD Non-coding RNAs, defined as functional RNA molecules (Arai et al. 2006; Neumann et al. 2006; Lagier-Tourenne that are not translated into a protein, may also contribute to et al. 2010). Mutant TARDBP mice models developed a the genesis of many human disorders (Table 1) (Esteller similar phenotype than human TARDBP mutation 2011). The best characterized ncRNAs in human condi- (Wegorzewska et al. 2009). Interestingly, no cytoplasmic tions are microRNAs (miRNAs) (Croce 2009), although aggregates were found in mice mutants; suggesting that other ncRNAs members are emerging, such as small other mechanisms rather than toxic cytoplasmic aggrega- nucleolar RNAs (snoRNAs), PIWI-interacting RNAs tion are underlying the molecular basis of ALS degenera- (piRNAs), large intergenic non-coding RNAs (lincRNAs), tion (Wegorzewska et al. 2009). Results are in accordance long non-coding RNAs (lncRNAs) and transcribed ultra- with a recent paper in which TDP-43 depletion in differ- conserved regions (T-UCRs), among others. If we focus on entiated Neruo2a results in decreased expression of miR- miRNAs biogenesis, miRNAs are transcribed as individual 132-3p and miR-132-5p. Further research of the specific units (named primary miRNA (pri-miRNA)). After pro- involvement of the aforementioned miRNAS (and others to cessing by the Drosha complex, precursor miRNAs (pre- be explored) will strongly contribute to the understanding miRNAs) are exported from the nucleus by the protein of the pathogenesis of ALS10. exportin 5 (XPO5). Further processing by Dicer and TAR RNA-binding protein 2 (TARBP2) generates mature DGCR8 mutations and DiGeorge syndrome miRNAs, which are included into the RNA-induced silencing complex (RISC). Once in this complex, miRNAs DiGeorge syndrome (MIM #188400) is a complex disorder could exert their function through degradation of protein- characterized by learning disabilities, characteristic facial coding transcripts or by translational repression. ncRNAs appearance, submucous cleft palate, conotruncal heart profiles are frequently disrupted in different types of cancer defects, thymic hypoplasia or aplasia, neonatal hypocal- and in non-tumoral disorders, such as imprinting disorders, cemia, psychiatric illness and susceptibility to infection rheumatoid arthritis, Rett syndrome and Alzheimer’s dis- due to a deficit of T cells (Goodship et al. 1998; Shiohama ease (Esteller 2011). Widespread alterations of ncRNAs et al. 2003). DiGeorge syndrome is caused by a 1.5 to 3.0- profiles could be also a consequence of genetic mutations Mb hemizygous deletion of chromosome 22q11.2 com- of the ncRNA-associated machinery. Some recent exam- prising the DiGeorge syndrome critical region gene 8 ples in this area are discussed in this section. (DGCR8) (Shiohama et al. 2003) that encodes a double stranded RNA-binding protein that is essential for miRNA TARDBP mutations and amyotrophic lateral sclerosis biogenesis. Specifically, DGCR8 is required in miRNA 10 with or without frontotemporal lobar degeneration maturation for processing pri-miRNAs to release pre- miRNAs in the nucleus (Han et al. 2006). Genetic modified Amyotrophic lateral sclerosis 10 (ALS10, MIM #612069) mouse models carrying a hemizygous chromosomal defi- with or without frontotemporal lobar degeneration (FTLD) ciency on chromosome 16 that spans a segment syntenic to 123 374 Hum Genet (2013) 132:359–383 the 1.5-Mb 22q11.2 microdeletion showed alterations in with histone deacetylase (HDAC) inhibitors, including the biogenesis of a set of miRNAs in the brain (Stark et al. SAHA (suberoylanilide hydroxamic acid), valproic acid 2008). Furthermore, DGCR8 deficiency resulted in altera- (VPA) and trichostatin A (TSA). Indeed, some of these tions of dendritic morphology, impaired sensorimotor gatin drugs have significant antitumoral activity and the FDA has and memory alterations similar to human DiGeorge phe- approved the use of several of them for treating patients notype (Stark et al. 2008). Additionally, it has been also (Kaminskas et al. 2005; Fiskus et al. 2008; Scuto et al. described that inactivation of a Dgcr8 conditional allele in 2008). This approval has sparked a dramatic increase in the neural crest cells results in cardiovascular defects (Chapnik development and trials of ‘‘epigenetic drugs’’ for treating et al. 2012). Similar results have been found in DGCR8 cancer and neural diseases (Kazantsev and Thompson conditional knock-out mice embryos and knockout vascu- 2008; Heyn and Esteller 2012). Although the most lar smooth muscle cells (Chen et al. 2012a, b). DGCR8 advanced clinical trials are those corresponding to cancer deficiency was associated with down-regulation of the treatment, interest has grown in the fields of neurological miR-17/92 and miR-143/145 clusters in vascular smooth and neurodegenerative diseases in recent years (Day and muscle cells, reduced cell proliferation and increased Sweatt 2012). The possibilities have only just begun to be apoptosis (Chen et al. 2012a, b). These data provide spe- explored in human patients, but the basis of this therapy cific explanations for cardiovascular and neuronal defects has been confirmed in animal models. that could explain, at least in part, the DiGeorge syndrome Rubinstein–Taybi syndrome (RSTS) is probably the best phenotype. model for studying the therapeutic uses of HDAC inhibi- tors that could compensate for the deficiency of HAT DICER mutations in multinodular 1 Goiter disease activity (CBP mutations). RSTS has been modeled in mice, and several heterozygous cbp ± mice (homozygous Autosomal dominant multinodular Goiter (MNG, MIM cbp -/- mutants are embryonic lethal) have been gener- #138800) is a disorder characterized by nodular over- ated (Alarcon et al. 2004). These models feature deficits in growth of the thyroid gland. In MNG type 1, some females long-term memory and cognitive impairments reminiscent may also develop Sertoli–Leydig ovary tumors (Rio Frio of human RTS neural symptoms, confirming the role of et al. 2011). Heterozygous mutations in DICER, a gene CBP in the etiology of the disease. At the molecular level, encoding an RNase III endonuclease essential for micr- these mice have reduced HAT activity, decreased acetyla- oRNA processing, have recently been linked to MNG tion of specific histone proteins and impaired CBP-depen- pathogenesis (Rio Frio et al. 2011). Mutations in DICER dent gene expression (Alarcon et al. 2004). Treatment with are also associated with pleuropulmonary blastoma (Hill HDAC inhibitors, such as SAHA or TSA, ameliorate defi- et al. 2009) and play a critical role in normal cardiac cits in synaptic plasticity and cognition in cbp ± mice function (Chen et al. 2008). DICER contains two RNase III (Hallam and Bourtchouladze 2006; Vecsey et al. 2007)by domains and a PAZ domain, a module that binds the end of enhancing transcriptional expression of specific neuronal double-strand RNA (Macrae et al. 2006). Familial MNG genes. In a similar manner, immortalized human lympho- shows clear selective disruption of the PAZ domain, sug- cytes derived from patients with RSTS showed reduced gesting a potential role of this domain in thyroid devel- acetylation levels, which primarily affect histones H2A and opment (Rio Frio et al. 2011). At the functional level, H2B, compared to the histone acetylation levels of lymphoblasts taken from MNG patients showed altered immortalized human lymphocytes derived from patients miRNA compared with control profiles (i.e., LET7A and with Cornelia de Lange syndrome (a neurological disorder) miR345), suggesting a dysregulation of gene expression or healthy controls (Lopez-Atalaya et al. 2012). Interest- patterns (Rio Frio et al. 2011). Further determination of the ingly, the acetylation deficits in RSTS cells were rescued by consequences of specific microRNAs synthesis could be an treatment with TSA (Lopez-Atalaya et al. 2012). important topic for future research into MNG and other Some therapeutic approaches have been investigated in DICER-associated pathologies. Rett syndrome. Mecp2 knock-out mice also exhibit the neurodevelopmental phenotype characteristic of human Therapeutic applications of epigenetics Rett syndrome (Shahbazian et al. 2002). The cognitive defect of MeCp2-deficient mice can be reverted by MecP2- One of the main characteristics of epigenetic mechanisms induced overexpression in mice (Collins et al. 2004) and in is their reversibility, making them potentially powerful MeCp2-deficient astrocytes (Lioy et al. 2011), suggesting tools for curative pharmacological therapy (Fig. 1). Reac- that this might well be an effective treatment for Rett tivation of epigenetically silenced genes has been possible syndrome. Apart from this gene therapy strategy, which is for years by the treatment with DNA demethylation drugs, not really applicable in humans, pharmacological treat- such as zebularine or 5-aza-20-deoxycytidine (5-ADC), or ments based on epigenetic targets are beginning to be 123 Hum Genet (2013) 132:359–383 375 explored as more feasible therapeutic interventions. Since treatment of human disorders associated with epigenetic MeCP2 binds directly to methylated promoters in associ- alterations. ation with the corepressor complex Sin3 and HDAC, another therapeutic strategy could be based on targeting Acknowledgments This work was supported by grants from the HDAC activity. It has been widely demonstrated that European Research Council (Advanced EPINORC), the Fondo de Investigaciones Sanitarias (PI08-1345 and PI10/02267), the Ministe- HDAC inhibitors enhance memory formation and neuronal rio de Ciencia e Innovacio´n (SAF2011-22803), the Fundacio´ La postnatal formation in various experimental models Marato´ de TV3 (111430/31), European COST Action TD09/05, and (Kazantsev and Thompson 2008). There are some exam- the Health Department of the Catalan Government (Generalitat de ples of the benefits of such treatments in the literature: the Catalunya). M.E. is an Institucio´ Catalana de Recerca i Estudis Avanc¸ats Research Professor. alleviation of motor deficits in mouse models of Hunting- ton disease by injections of SAHA (Hockly et al. 2003); the delay of neurodegeneration and tauopathy in a mouse model of Alzheimer’s disease through the activation of References SIRT1 by means of resveratrol treatments (Kilgore et al. Aapola U, Liiv I, Peterson P (2002) Imprinting regulator DNMT3L is 2010); and the reactivation of the frataxin genes by treat- a transcriptional repressor associated with histone deacetylase ments with benzamide-based HDAC inhibitors in immor- activity. Nucleic Acids Res 30(16):3602–3608 talized cultured cells from Friedrich’s Ataxia syndrome Abidi FE, Cardoso C, Lossi AM, Lowry RB, Depetris D, Mattei MG, patients (Herman et al. 2006). Lubs HA, Stevenson RE, Fontes M, Chudley AE, Schwartz CE (2005) Mutation in the 5-prime alternatively spliced region of However, many questions remain unsolved concerning the XNP/ATR-X gene causes Chudley-Lowry syndrome. Europ drug potency, selectivity and permeability. Treatment with J Hum Genet 13:176–183 HDAC inhibitors results in the re-expression of a limited Abidi FE, Miano MG, Murray JC, Schwartz CE (2007) A novel number of memory-associated genes (Vecsey et al. 2007). mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate. Clin Genet 72:19–22 This raises a question: are HDAC inhibitors’ treatments Abidi FE, Holloway L, Moore CA, Weaver DD, Simensen RJ, potentially able to restore all types of genes? Or by contrast Stevenson RE, Rogers RC, Schwartz CE (2008) Mutations in do more ‘‘easier reverted’’ genes exist that can be phar- JARID1C are associated with X-linked mental retardation, short macologically manipulated? If reversion is conditioned to stature and hyperreflexia. J Med Genet 45:787–793 Alarcon JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER, any factor (i.e., their genomic context or the acetylation Barco A (2004) Chromatin acetylation, memory, and LTP are level) HDAC treatments would be more effective in certain impaired in CBP ± mice: a model for the cognitive defect in diseases than others. Multiple epigenetic enzymes could Rubinstein-Taybi syndrome and its amelioration. Neuron contribute to a specific mark (especially histone acetyla- 42:947–959 Aldred MA, Sanford ROC, Thomas NS, Barrow MA, Wilson LC, tion) and furthermore, manipulating histone modifications Brueton LA, Bonaglia MC, Hennekam RCM, Eng C, Dennis could also affect DNA methylation. Which is the best NR, Trembath RC (2004) Molecular analysis of 20 patients with target for inducing specific gene re-expression? Should 2q37.3 monosomy: definition of minimum deletion intervals for systemic or enzyme-targeted drugs be employed? This lack key phenotypes. J Med Genet 41:433–439 Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi of specificity means that almost none of the available HY (1999) Rett syndrome is caused by mutations in X-linked epigenetic drugs are isoform-specific and, for instance, MECP2, encoding methyl-CpG-binding protein 2. Nat Genet HDAC inhibitors have binding affinities for different 23(2):185–188 HDACs isoforms (Kilgore et al. 2010). It is expected that Anindya R, Mari PO, Kristensen U, Kool H, Giglia-Mari G, Mullenders LH, Fousteri M, Vermeulen W, Egly JM, Svejstrup development of subclass-specific inhibitors might contrib- JQ (2010) A ubiquitin-binding domain in Cockayne syndrome B ute to minimize the side effects of the epigenetic therapy. required for transcription-coupled nucleotide excision repair. On the other hand, the tissue also influences its effective- Mol Cell 38(5):637–648 ness. DNA demethylating drugs are deoxycytidine analogs Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 that must be incorporated into the DNA after replication is a component of ubiquitin-positive tau-negative inclusions in cycles. As a consequence, the ‘‘speed’’ of base substitution frontotemporal lobar degeneration and amyotrophic lateral is strongly influenced by the rate of cell division. It is to be sclerosis. Biochem Biophys Res Commun 351(3):602–611 expected that such DNA demethylating treatments will not Arany Z, Sellers WR, Livingston DM, Eckner R (1994) E1A- associated p300 and CREB-associated CBP belong to a be very effective in neuronal cells with few or no cell conserved family of coactivators. Cell 77(6):799–800 divisions. Further knowledge about the pathogenesis and Argentaro A, Yang JC, Chapman L, Kowalczyk MS, Gibbons RJ, identification of the molecular/regulatory pathways that are Higgs DR, Neuhaus D, Rhodes D (2007) Structural conse- altered in the disease will enable the optimal target to be quences of disease-causing mutations in the ATRX-DNMT3- DNMT3L (ADD) domain of the chromatin-associated protein identified and the therapeutic potential of epigenetic-based ATRX. Proc Natl Acad Sci USA 104(29):11939–11944 drugs to be exploited. Despite these difficulties, epigenetic- Arnold MA, Kim Y, Czubryt MP, Phan D, McAnally J, Qi X, Shelton based therapy may become a successful intervention in the JM, Richardson JA, Bassel-Duby R, Olson EN (2007) MEF2C 123 376 Hum Genet (2013) 132:359–383

transcription factor controls chondrocyte hypertrophy and bone genitopatellar syndrome and Ohdo/SBBYS syndrome have development. Dev Cell 12(3):377–389 distinct clinical features reflecting distinct molecular mecha- Aziz A, Liu QC, Dilworth FJ (2010) Regulating a master regulator: nisms. Hum Mutat 33(11):1520–1525 establishing tissue-specific gene expression in skeletal muscle. Carney RM, Wolpert CM, Ravan SA, Shahbazian M, Ashley-Koch A, Epigenetics 5(8):691–695 Cuccaro ML, Vance JM, Pericak-Vance MA (2003) Identifica- Bajpai R, Chen DA, Rada-Iglesias A, Zhang J, Xiong Y, Helms J, tion of MeCP2 mutations in a series of females with autistic Chang CP, Zhao Y, Swigut T, Wysocka J (2010) CHD7 disorder. Pediat Neurol 28:205–211 cooperates with PBAF to control multipotent neural crest Chahrour M, Jung SY, Shaw C, Zhou X, Wong ST, Qin J, Zoghbi HY formation. Nature 463(7283):958–962 (2008) MeCP2, a key contributor to neurological disease, Ballas N, Lioy DT, Grunseich C, Mandel G (2009) Non-cell activates and represses transcription. Science 320(5880): autonomous influence of MeCP2-deficient glia on neuronal 1224–1229 dendritic morphology. Nat Neurosci 12(3):311–317 Champagne N, Bertos NR, Pelletier N, Wang AH, Vezmar M, Yang Bannister AJ, Kouzarides T (2011) Regulation of chromatin by Y, Heng HH, Yang XJ (1999) Identification of a human histone histone modifications. Cell Res 21(3):381–395 acetyltransferase related to monocytic leukemia zinc finger Bartholdi D, Roelfsema JH, Papadia F, Breuning MH, Niedrist D, protein. J Biol Chem 274:28528–28536 Hennekam RC, Schinzel A, Peters DJ (2007) Genetic heteroge- Chan HM, La Thangue NB (2001) p300/CBP proteins: HATs for neity in Rubinstein-Taybi syndrome: delineation of the pheno- transcriptional bridges and scaffolds. J Cell Sci 114:2363–2373 type of the first patients carrying mutations in EP300. J Med Chang Q, Khare G, Dani V, Nelson S, Jaenisch R (2006) The disease Genet 44(5):327–333 progression of Mecp2 mutant mice is affected by the level of Bartsch O, Labonte J, Albrecht B, Wieczorek D, Lechno S, Zechner BDNF expression. Neuron 49(3):341–348 U, Haaf T (2010) Two patients with EP300 mutations and facial Chapnik E, Sasson V, Blelloch R, Hornstein E (2012) Dgcr8 controls dysmorphism different from the classic Rubinstein-Taybi neural crest cells survival in cardiovascular development. Dev syndrome. Am J Med Genet 152A:181–184 Biol 362(1):50–56 Basel-Vanagaite L (2010) Acute lymphoblastic leukemia in Weaver Chen B, Cepko CL (2009) HDAC4 regulates neuronal survival in syndrome. Am J Med Genet 152A:383–386 normal and diseased retinas. Science 323(5911):256–259 Batenburg NL, Mitchell TR, Leach DM, Rainbow AJ, Zhu XD (2012) Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, Cockayne Syndrome group B protein interacts with TRF2 and Rojas M, Hammond SM, Schneider MD, Selzman CH, Meissner regulates telomere length and stability. Nucleic Acids Res G, Patterson C, Hannon GJ, Wang DZ (2008) Targeted deletion 40(19):9661–9674 of Dicer in the heart leads to dilated cardiomyopathy and heart Baujat G, Rio M, Rossignol S, Sanlaville D, Lyonnet S, Le Merrer M, failure. Proc Natl Acad Sci USA 105(6):2111–2116 Munnich A, Gicquel C, Cormier-Daire V, Colleaux L (2004) Chen H, Gu X, Su IH, Bottino R, Contreras JL, Tarakhovsky A, Kim Paradoxical NSD1 mutations in Beckwith-Wiedemann syn- SK (2009) Polycomb protein Ezh2 regulates pancreatic beta-cell drome and 11p15 anomalies in Sotos syndrome. Am J Hum Ink4a/Arf expression and regeneration in diabetes mellitus. Genet 74:715–720 Genes Dev 23(8):975–985 Berdasco M, Esteller M (2010) Aberrant epigenetic landscape in Chen YC, Gatchel JR, Lewis RW, Mao CA, Grant PA, Zoghbi HY, cancer: how cellular identity goes awry. Dev Cell 19(5):698–711 Dent SY (2012a) Gcn5 loss-of-function accelerates cerebellar Berdasco M, Esteller M (2011) DNA methylation in stem cell renewal and retinal degeneration in a SCA7 mouse model. Hum Mol and multipotency. Stem Cell Res Ther 2(5):42 Genet 21(2):394–405 Berdasco M, Ropero S, Setien F, Fraga MF, Lapunzina P, Losson R, Chen Z, Wu J, Yang C, Fan P, Balazs L, Jiao Y, Lu M, Gu W, Li C, Alaminos M, Cheung NK, Rahman N, Esteller M (2009) Pfeffer LM, Tigyi G, Yue J (2012b) DiGeorge syndrome critical Epigenetic inactivation of the Sotos overgrowth syndrome gene region 8 (DGCR8) protein-mediated microRNA biogenesis is histone methyltransferase NSD1 in human neuroblastoma and essential for vascular smooth muscle cell development in mice. glioma. Proc Natl Acad Sci USA 106(51):21830–21835 J Biol Chem 287(23):19018–19028 Berquist BR, Canugovi C, Sykora P, Wilson DM 3rd, Bohr VA Chou RH, Yu YL, Hung MC (2011) The roles of EZH2 in cell lineage (2012) Human Cockayne syndrome B protein reciprocally commitment. Am J Transl Res 3(3):243–250 communicates with mitochondrial proteins and promotes tran- Chrivia JC, Kwok RP, Lamb N, Hagiwara M, Montminy MR, scriptional elongation. Nucleic Acids Res 40(17):8392–8405 Goodman RH (1993) Phosphorylated CREB binds specifically to Bourtchouladze R, Lidge R, Catapano R, Stanley J, Gossweiler S, the nuclear protein CBP. Nature 365:855–859 Romashko D, Scott R, Tully T (2003) A mouse model of Claes S, Devriendt K, Van Goethem G, Roelen L, Meireleire J, Rubinstein-Taybi syndrome: defective long-term memory is Raeymaekers P, Cassiman JJ, Fryns JP (2000) Novel syndromic ameliorated by inhibitors of phosphodiesterase 4. Proc Natl Acad form of X-linked complicated spastic paraplegia. Am J Med Sci USA 100:10518–10522 Genet 94:1–4 Brun ME, Lana E, Rivals I, Lefranc G, Sarda P, Claustres M, Clayton-Smith J, O’Sullivan J, Daly S, Bhaskar S, Day R, Anderson Me´garbane´ A, De Sario A (2011) Heterochromatic genes B, Voss AK, Thomas T, Biesecker LG, Smith P, Fryer A, undergo epigenetic changes and escape silencing in immunode- Chandler KE, Kerr B, Tassabehji M, Lynch SA, Krajewska- ficiency, centromeric instability, facial anomalies (ICF) syn- Walasek M, McKee S, Smith J, Sweeney E, Mansour S, drome. PLoS ONE 6(4):e19464 Mohammed S, Donnai D, Black G (2011) Whole-exome- Campeau PM, Kim JC, Lu JT, Schwartzentruber JA, Abdul-Rahman sequencing identifies mutations in histone acetyltransferase gene OA, Schlaubitz S, Murdock DM, Jiang MM, Lammer EJ, Enns KAT6B in individuals with the Say-Barber-Biesecker variant of GM, Rhead WJ, Rowland J, Robertson SP, Cormier-Daire V, Ohdo syndrome. Am J Hum Genet 89:675–681 Bainbridge MN, Yang XJ, Gingras MC, Gibbs RA, Rosenblatt Collins AL, Levenson JM, Vilaythong AP, Richman R, Armstrong DS, Majewski J, Lee BH (2012a) Mutations in KAT6B, DL, Noebels JL, David Sweatt J, Zoghbi HY (2004) Mild encoding a histone acetyltransferase, cause Genitopatellar syn- overexpression of MeCP2 causes a progressive neurological drome. Am J Hum Genet 90(2):282–289 disorder in mice. Hum Mol Genet 13(21):2679–2689 Campeau PM, Lu JT, Dawson BC, Fokkema IF, Robertson SP, Croce CM (2009) Causes and consequences of microRNA dysreg- Gibbs RA, Lee BH (2012b) The KAT6B-related disorders ulation in cancer. Nat Rev Genet 10(10):704–714

123 Hum Genet (2013) 132:359–383 377

Das C, Lucia MS, Hansen KC, Tyler JK (2009) CBP/p300-mediated embryo revealed using RNAi of ovary-enriched ORFeome acetylation of histone H3 on lysine 56. Nature 459(7243): clones. Genome Res 15(2):250–259 113–117 Fiskus W, Wang Y, Joshi R, Rao R, Yang Y, Chen J, Kolhe R, Balusu Day JJ, Sweatt JD (2012) Epigenetic treatments for cognitive R, Eaton K, Lee P, Ustun C, Jillella A, Buser CA, Peiper S, impairments. Neuropsychopharmacology 37(1):247–260 Bhalla K (2008) Cotreatment with vorinostat enhances activity De Felice C, Signorini C, Leoncini S, Pecorelli A, Durand T, Valacchi of MK-0457 (VX-680) against acute and chronic myelogenous G, Ciccoli L, Hayek J (2012) The role of oxidative stress in Rett leukemia cells. Clin Cancer Res 14(19):6106–6115 syndrome: an overview. Ann N Y Acad Sci 1259(1):121–135 Flaus A, Owen-Hughes T (2011) Mechanisms for ATP-dependent De Greef JC, Wang J, Balog J, den Dunnen JT, Frants RR, chromatin remodelling: the means to the end. FEBS J Straasheijm KR, Aytekin C, van der Burg M, Duprez L, Ferster 278(19):3579–3595 A, Gennery AR, Gimelli G, Reisli I, Schuetz C, Schulz A, Franklin TB, Mansuy IM (2011) The involvement of epigenetic Smeets DF, Sznajer Y, Wijmenga C, van Eggermond MC, van defects in mental retardation. Neurobiol Learn Mem 96(1):61–67 Ostaijen-Ten Dam MM, Lankester AC, van Tol MJ, van den Froyen G, Bauters M, Voet T, Marynen P (2006) X-linked mental Elsen PJ, Weemaes CM, van der Maarel SM (2011) Mutations in retardation and epigenetics. J Cell Mol Med 10(4):808–825 ZBTB24 are associated with immunodeficiency, centromeric Garden GA, La Spada AR (2008) Molecular pathogenesis and cellular instability, and facial anomalies syndrome type 2. Am J Hum pathology of spinocerebellar ataxia type 7 neurodegeneration. Genet 88(6):796–804 Cerebellum 7(2):138–149 Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain Giacometti E, Luikenhuis S, Beard C, Jaenisch R (2007) Partial protein superfamily: protein lysine methyltransferases. Genome rescue of MeCP2 deficiency by postnatal activation of MeCP2. Biol 6(8):227 Proc Natl Acad Sci USA 104(6):1931–1936 Douglas J, Hanks S, Temple IK, Davies S, Murray A, Upadhyaya M, Gibbons RJ, Picketts DJ, Villard L, Higgs DR (1995) Mutations in a Tomkins S, Hughes HE, Cole TR, Rahman N (2003) NSD1 putative global transcriptional regulator cause X-linked mental mutations are the major cause of Sotos syndrome and occur in retardation with alpha-thalassemia (ATR-X syndrome). Cell some cases of Weaver syndrome but are rare in other overgrowth 80:837–845 phenotypes. Am J Hum Genet 72(1):132–143 Gibbons RJ, McDowell TL, Raman S, O’Rourke DM, Garrick D, Ea CK, Hao S, Yeo KS, Baltimore D (2012) EHMT1 binds to NF-jB Ayyub H, Higgs DR (2000) Mutations in ATRX, encoding a p50 and represses gene expression. J Biol Chem 287(37): SWI/SNF-like protein, cause diverse changes in the pattern of 31207–31217 DNA methylation. Nat Genet 24:368–371 Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Gibbons RJ, Pellagatti A, Garrick D, Wood WG, Malik N, Ayyub H, Lawrence JB, Livingston DM (1994) Molecular cloning and Langford C, Boultwood J, Wainscoat JS, Higgs DR (2003) functional analysis of the adenovirus E1A-associated 300-kD Identification of acquired somatic mutations in the gene encod- protein (p300) reveals a protein with properties of a transcrip- ing chromatin-remodeling factor ATRX in the alpha-thalassemia tional adaptor. Genes Dev 8:869–884 myelodysplasia syndrome (ATMDS). Nat Genet 34:446–449 Edbauer D, Neilson JR, Foster KA, Wang CF, Seeburg DP, Batterton Gibson WT, Hood RL, Zhan SH, Bulman DE, Fejes AP, Moore R, MN, Tada T, Dolan BM, Sharp PA, Sheng M (2010) Regulation Mungall AJ, Eydoux P, Babul-Hirji R, An J, Marra MA, FORGE of synaptic structure and function by FMRP-associated microR- Canada Consortium, Chitayat D, Boycott KM, Weaver DD, NAs miR-125b and miR-132. Neuron 65(3):373–384 Jones SJM (2012) Mutations in EZH2 cause Weaver syndrome. Ehrlich M (2003) The ICF syndrome, a DNA methyltransferase 3B Am J Hum Genet 90:110–118 deficiency and immunodeficiency disease. Clin Immunol Goldberg AD, Banaszynski LA, Noh KM, Lewis PW, Elsaesser SJ, 109:17–28 Stadler S, Dewell S, Law M, Guo X, Li X, Wen D, Chapgier A, Eissenberg JC, Wong M, Chrivia JC (2005) Human SRCAP and DeKelver RC, Miller JC, Lee YL, Boydston EA, Holmes MC, Drosophila melanogaster DOM are homologs that function in the Gregory PD, Greally JM, Rafii S, Yang C, Scambler PJ, Garrick notch signaling pathway. Mol Cell Biol 25(15):6559–6569 D, Gibbons RJ, Higgs DR, Cristea IM, Urnov FD, Zheng D Erdel F, Rippe K (2011) Chromatin remodelling in mammalian cells (2010) Allis CD (2010) Distinct factors control histone variant by ISWI-type complexes–where, when and why? FEBS J H3.3 localization at specific genomic regions. Cell 278(19):3608–3618 140(5):678–691 Esteller M (2008) Epigenetics in cancer. N Engl J Med Goodship J, Cross I, LiLing J, Wren C (1998) A population study of 358(11):1148–1159 chromosome 22q11 deletions in infancy. Arch Dis Child Esteller M (2011) Non-coding RNAs in human disease. Nat Rev 79:348–351 Genet 12(12):861–874 Guy J, Gan J, Selfridge J, Cobb S, Bird A (2007) Reversal of Etchegaray JP, Yang X, DeBruyne JP, Peters AH, Weaver DR, neurological defects in a mouse model of Rett syndrome. Jenuwein T, Reppert SM (2006) The polycomb group protein Science 315(5815):1143–1147 EZH2 is required for mammalian circadian clock function. J Biol Hallam TM, Bourtchouladze R (2006) Rubinstein-Taybi syndrome: Chem 281(30):21209–21215 molecular findings and therapeutic approaches to improve Fatemi M, Hermann A, Pradhan S, Jeltsch A (2001) The activity of cognitive dysfunction. Cell Mol Life Sci 63:1725–1735 the murine DNA methyltransferase Dnmt1 is controlled by Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, interaction of the catalytic domain with the N-terminal part of Zhang BT, Kim VN (2006) Molecular basis for the recognition the enzyme leading to an allosteric activation of the enzyme after of primary microRNAs by the Drosha-DGCR8 complex. Cell binding to methylated DNA. J Mol Biol 309(5):1189–1199 125(5):887–901 Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, Silva AJ, Fan G Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin (2010) Dnmt1 and Dnmt3a maintain DNA methylation and MJ, Gildersleeve HI, Bigham AW, Tabor HK, Mefford HC, regulate synaptic function in adult forebrain neurons. Nat Cook J, Yoshiura K, Matsumoto T, Matsumoto N, Miyake N, Neurosci 13(4):423–430 Tonoki H, Naritomi K, Kaname T, Nagai T, Ohashi H, Fernandez AG, Gunsalus KC, Huang J, Chuang LS, Ying N, Liang Kurosawa K, Hou JW, Ohta T, Liang D, Sudo A, Morris CA, HL, Tang C, Schetter AJ, Zegar C, Rual JF, Hill DE, Reinke V, Banka S, Black GC, Clayton-Smith J, Nickerson DA, Zackai Vidal M, Piano F (2005) New genes with roles in the C. elegans EH, Shaikh TH, Donnai D, Niikawa N, Shendure J, Bamshad MJ

123 378 Hum Genet (2013) 132:359–383

(2011) Spectrum of MLL2 (ALR) mutations in 110 cases of Huang N, vom Baur E, Garnier JM, Lerouge T, Vonesch JL, Lutz Y, Kabuki syndrome. Am J Med Genet 155A:1511–1516 Chambon P, Losson R (1998) Two distinct nuclear receptor Hargreaves DC, Crabtree GR (2011) ATP-dependent chromatin interaction domains in NSD1, a novel SET protein that exhibits remodeling: genetics, genomics and mechanisms. Cell Res characteristics of both corepressors and coactivators. EMBO J 21(3):396–420 17(12):3398–3412 Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio Hurd EA, Poucher HK, Cheng K, Raphael Y, Martin DM (2010) The D, Wang L, Craig JM, Jones PL, Sif S, El-Osta A (2005) Brahma ATP-dependent chromatin remodeling enzyme CHD7 regulates links the SWI/SNF chromatin-remodeling complex with pro-neural gene expression and neurogenesis in the inner ear. MeCP2-dependent transcriptional silencing. Nat Genet 37: Development 137(18):3139–3150 254–264 Ishibashi T, Thambirajah AA, Ausio´ J (2008) MeCP2 preferentially Helmlinger D, Hardy S, Abou-Sleymane G, Eberlin A, Bowman AB, binds to methylated linker DNA in the absence of the terminal Gansmu¨ller A, Picaud S, Zoghbi HY, Trottier Y, Tora L, Devys tail of histone H3 and independently of histone acetylation. D (2006) Glutamine-expanded ataxin-7 alters TFTC/STAGA FEBS Lett 582(7):1157–1162 recruitment and chromatin structure leading to photoreceptor Jensen LR, Amende M, Gurok U, Moser B, Gimmel V, Tzschach A, dysfunction. PLoS Biol 4(3):e67 Janecke AR, Tariverdian G, Chelly J, Fryns JP, Van Esch H, Hennekam RCM (2006) Rubinstein-Taybi syndrome. Europ. J Hum Kleefstra T, Hamel B, Moraine C, Gecz J, Turner G, Reinhardt Genet 14:981–985 R, Kalscheuer VM, Ropers HH, Lenzner S (2005) Mutations in Henning KA, Li L, Iyer N, McDaniel LD, Reagan MS, Legerski R, the JARID1C gene, which is involved in transcriptional regu- Schultz RA, Stefanini M, Lehmann AR, Mayne LV, Friedberg lation and chromatin remodeling, cause X-linked mental retar- EC (1995) The Cockayne syndrome group A gene encodes a WD dation. Am J Hum Genet 76:227–236 repeat protein that interacts with CSB protein and a subunit of Jiang X, Zhou Y, Xian L, Chen W, Wu H, Gao X (2012) The RNA polymerase II TFIIH. Cell 82:555–564 mutation in Chd7 causes misexpression of Bmp4 and develop- Herman D, Jenssen K, Burnett R, Soragni E, Perlman SL, Gottesfeld mental defects in telencephalic midline. Am J Pathol 181(2): JM (2006) Histone deacetylase inhibitors reverse gene silencing 626–641 in Friedreich’s ataxia. Nat Chem Biol 2(10):551–558 Jin B, Tao Q, Peng J, Soo HM, Wu W, Ying J, Fields CR, Delmas Heyn H, Esteller M (2012) DNA methylation profiling in the clinic: AL, Liu X, Qiu J, Robertson KD (2008) DNA methyltransferase applications and challenges. Nat Rev Genet 13(10):679–692 3B (DNMT3B) mutations in ICF syndrome lead to altered Heyn H, Vidal E, Sayols S, Sanchez-Mut JV, Moran S, Medina I, epigenetic modifications and aberrant expression of genes Sandoval J, Simo´-Riudalbas L, Szczesna K, Huertas D, Gatto S, regulating development, neurogenesis and immune function. Matarazzo MR, Dopazo J, Esteller M (2012) Whole-genome Hum Mol Genet 17(5):690–709 bisulfite DNA sequencing of a DNMT3B mutant patient. Jin Q, Yu LR, Wang L, Zhang Z, Kasper LH, Lee JE, Wang C, Epigenetics 7(6):542–550 Brindle PK, Dent SY, Ge K (2011) Distinct roles of GCN5/ Hill DA, Ivanovich J, Priest JR, Gurnett CA, Dehner LP, Desruisseau PCAF-mediated H3K9ac and CBP/p300-mediated H3K18/27ac D, Jarzembowski JA, Wikenheiser-Brokamp KA, Suarez BK, in nuclear receptor transactivation. EMBO J 30(2):249–262 Whelan AJ, Williams G, Bracamontes D, Messinger Y, Good- Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger fellow PJ (2009) DICER1 mutations in familial pleuropulmonary N, Strouboulis J, Wolffe AP (1998) Methylated DNA and blastoma. Science 325:965 MeCP2 recruit histone deacetylase to repress transcription. Nat Ho L, Crabtree GR (2010) Chromatin remodelling during develop- Genet 19(2):187–191 ment. Nature 463(7280):474–484 Josefowicz SZ, Wilson CB, Rudensky AY (2009) Cutting edge: TCR Ho L, Jothi R, Ronan JL, Cui K, Zhao K, Crabtree GR (2009) An stimulation is sufficient for induction of Foxp3 expression in the embryonic stem cell chromatin remodeling complex, esBAF, is absence of DNA methyltransferase 1. J Immunol 182(11): an essential component of the core pluripotency transcriptional 6648–6652 network. Proc Natl Acad Sci USA 106(13):5187–5191 Juan AH, Derfoul A, Feng X, Ryall JG, Dell’Orso S, Pasut A, Zare H, Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Simone JM, Rudnicki MA, Sartorelli V (2011) Polycomb EZH2 Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, controls self-renewal and safeguards the transcriptional identity Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP of skeletal muscle stem cells. Genes Dev 25(8):789–794 (2003) Suberoylanilide hydroxamic acid, a histone deacetylase Kaminskas E, Farrell A, Abraham S, Baird A, Hsieh LS, Lee SL, inhibitor, ameliorates motor deficits in a mouse model of Leighton JK, Patel H, Rahman A, Sridhara R, Wang YC, Pazdur Huntington’s disease. Proc Natl Acad Sci USA 100(4): R (2005) FDA, Approval summary: azacitidine for treatment of 2041–2046 myelodysplastic syndrome subtypes. Clin Cancer Res 11(10): Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (2007) 3604–3608 Identification of JmjC domain-containing UTX and JMJD3 as Kasper LH, Thomas MC, Zambetti GP, Brindle PK (2011) Double histone H3 lysine 27 demethylases. Proc Natl Acad Sci USA null cells reveal that CBP and p300 are dispensable for p53 104(47):18439–18444 targets p21 and Mdm2 but variably required for target genes of Hood RL, Lines MA, Nikkel SM, Schwartzentruber J, Beaulieu C, other signaling pathways. Cell Cycle 10(2):212–221 Nowaczyk MJ, Allanson J, Kim CA, Wieczorek D, Moilanen JS, Kawahara Y, Mieda-Sato A (2012) TDP-43 promotes microRNA Lacombe D, Gillessen-Kaesbach G, Whiteford ML, Quaio CR, biogenesis as a component of the Drosha and Dicer complexes. Gomy I, Bertola DR, Albrecht B, Platzer K, McGillivray G, Zou Proc Natl Acad Sci USA 109(9):3347–3352 R, McLeod DR, Chudley AE, Chodirker BN, Marcadier J, Kazantsev AG, Thompson LM (2008) Therapeutic application of FORGE Canada Consortium, Majewski J, Bulman DE, White histone deacetylase inhibitors for central nervous system disor- SM, Boycott KM (2012) Mutations in SRCAP, encoding SNF2- ders. Nat Rev Drug Discov 7(10):854–868 related CREBBP activator protein, cause Floating-Harbor syn- Kilgore M, Miller CA, Fass DM, Hennig KM, Haggarty SJ, Sweatt drome. Am J Hum Genet 90(2):308–313 JD, Rumbaugh G (2010) Inhibitors of class 1 histone Horike S, Cai S, Miyano M, Cheng JF, Kohwi-Shigematsu T (2005) deacetylases reverse contextual memory deficits in a mouse Loss of silent-chromatin looping and impaired imprinting of model of Alzheimer’s disease. Neuropsychopharmacology DLX5 in Rett syndrome. Nat Genet 37(1):31–40 35(4):870–880

123 Hum Genet (2013) 132:359–383 379

Kim HG, Kurth I, Lan F, Meliciani I, Wenzel W, Eom SH, Kang GB, MB, Keleman K, Zhou H, van Bokhoven H, Schenck A (2011) Rosenberger G, Tekin M, Ozata M, Bick DP, Sherins RJ, Walker Epigenetic regulation of learning and memory by Drosophila SL, Shi Y, Gusella JF, Layman LC (2008) Mutations in CHD7, EHMT/G9a. PLoS Biol 9(1):e1000569 encoding a chromatin-remodeling protein, cause idiopathic Kurotaki N, Harada N, Yoshiura K, Sugano S, Niikawa N, Matsumoto hypogonadotropic hypogonadism and Kallmann syndrome. Am N (2001) Molecular characterization of NSD1, a human J Hum Genet 83:511–519 homologue of the mouse Nsd1 gene. Gene 279(2):197–204 Kirmizis A, Bartley SM, Kuzmichev A, Margueron R, Reinberg D, Kurotaki N, Imaizumi K, Harada N, Masuno M, Kondoh T, Nagai T, Green R, Farnham PJ (2004) Silencing of human polycomb Ohashi H, Naritomi K, Tsukahara M, Makita Y, Sugimoto T, target genes is associated with methylation of histone H3 Lys 27. Sonoda T, Hasegawa T, Chinen Y, Tomita Ha HA, Kinoshita A, Genes Dev 18(13):1592–1605 Mizuguchi T, Yoshiura Ki K, Ohta T, Kishino T, Fukushima Y, Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Niikawa N, Matsumoto N (2002) Haploinsufficiency of NSD1 Houge G, Foulds N, van Dooren M, Willemsen MH, Pfundt R, causes Sotos syndrome. Nat Genet 30(4):365–366 Turner A, Wilson M, McGaughran J, Rauch A, Zenker M, Adam Lacombe D, Saura R, Taine L, Battin J (1992) Confirmation of MP, Innes M, Davies C, Lo´pez AG, Casalone R, Weber A, assignment of a locus for Rubinstein-Taybi syndrome gene to Brueton LA, Navarro AD, Bralo MP, Venselaar H, Stegmann 16p13.3. Am J Med Gent 44:126–128 SP, Yntema HG, van Bokhoven H, Brunner HG (2009) Further Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 clinical and molecular delineation of the 9q subtelomeric and FUS/TLS: emerging roles in RNA processing and neurode- deletion syndrome supports a major contribution of EHMT1 generation. Hum Mol Genet 19(R1):R46–R64 haploinsufficiency to the core phenotype. J Med Genet 46: Lan F, Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase 598–606 S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Kleefstra T, Brunner HG, Amiel J, Oudakker AR, Nillesen WM, Y (2007) A histone H3 lysine 27 demethylase regulates animal Magee A, Genevie`ve D, Cormier-Daire V, van Esch H, Fryns JP, posterior development. Nature 449(7163):689–694 Hamel BC, Sistermans EA, de Vries BB, van Bokhoven H Lana E, Me´garbane´ A, Tourrie`re H, Sarda P, Lefranc G, Claustres M, (2006) Loss-of-function mutations in euchromatin histone De Sario A (2012) DNA replication is altered in Immunodefi- methyl transferase 1 (EHMT1) cause the 9q34 subtelomeric ciency Centromeric instability Facial anomalies (ICF) cells deletion syndrome. Am J Hum Genet 79:370–377 carrying DNMT3B mutations. Eur J Hum Genet 20(10): Kleefstra T, Kramer JM, Neveling K, Willemsen MH, Koemans TS, 1044–1050 Vissers LE, Wissink-Lindhout W, Fenckova M, van den Akker Lapunzina P (2005) Risk of tumorigenesis in overgrowth syndromes: WM, Kasri NN, Nillesen WM, Prescott T, Clark RD, Devriendt a comprehensive review. Am J Med Genet C Semin Med Genet K, van Reeuwijk J, de Brouwer AP, Gilissen C, Zhou H, Brunner 137C(1):53–71 HG, Veltman JA, Schenck A, van Bokhoven H (2012) Disrup- Laugel V, Dalloz C, Durand M, Sauvanaud F, Kristensen U, Vincent tion of an EHMT1-Associated Chromatin-Modification Module MC, Pasquier L, Odent S, Cormier-Daire V, Gener B, Tobias ES, Causes Intellectual Disability. Am J Hum Genet 91(1):73–82 Tolmie JL, Martin-Coignard D, Drouin-Garraud V, Heron D, Klein CJ, Botuyan MV, Wu Y, Ward CJ, Nicholson GA, Hammans S, Journel H, Raffo E, Vigneron J, Lyonnet S, Murday V, Gubser- Hojo K, Yamanishi H, Karpf AR, Wallace DC, Simon M, Mercati D, Funalot B, Brueton L, Sanchez Del Pozo J, Mun˜oz E, Lander C, Boardman LA, Cunningham JM, Smith GE, Litchy Gennery AR, Salih M, Noruzinia M, Prescott K, Ramos L, Stark WJ, Boes B, Atkinson EJ, Middha S, Dyck B, Parisi JE, Mer G, Z, Fieggen K, Chabrol B, Sarda P, Edery P, Bloch-Zupan A, Smith DI, Dyck PJ (2011) Mutations in DNMT1 cause Fawcett H, Pham D, Egly JM, Lehmann AR, Sarasin A, Dollfus hereditary sensory neuropathy with dementia and hearing loss. H (2010) Mutation update for the CSB/ERCC6 and CSA/ERCC8 Nat Genet 43:595–600 genes involved in Cockayne syndrome. Hum Mutat 31(2): Kleine-Kohlbrecher D, Christensen J, Vandamme J, Abarrategui I, 113–126 Bak M, Tommerup N, Shi X, Gozani O, Rappsilber J, Salcini Laumonnier F, Holbert S, Ronce N, Faravelli F, Lenzner S, Schwartz AE, Helin K (2010) A Functional Link between the Histone CE, Lespinasse J, Van Esch H, Lacombe D, Goizet C, Phan- Demethylase PHF8 and the Transcription Factor ZNF711 in Dinh Tuy F, van Bokhoven H, Fryns JP, Chelly J, Ropers HH, X-Linked Mental Retardation. Mol Cell 38(2–2):165–178 Moraine C, Hamel BC, Briault S (2005) Mutations in PHF8 are Koivisto AM, Ala-Mello S, Lemmela¨ S, Komu HA, Rautio J, Ja¨rvela¨ associated with X linked mental retardation and cleft lip/cleft I (2007) Screening of mutations in the PHF8 gene and palate. J Med Genet 42:780–786 identification of a novel mutation in a Finnish family with Law MJ, Lower KM, Voon HP, Hughes JR, Garrick D, Viprakasit V, XLMR and cleft lip/cleft palate. Clin Genet 72:145–149 Mitson M, De Gobbi M, Marra M, Morris A, Abbott A, Wilder Korzus E, Rosenfeld MG, Mayford M (2004) CBP histone acetyl- SP, Taylor S, Santos GM, Cross J, Ayyub H, Jones S, Ragoussis transferase activity is a critical component of memory consol- J, Rhodes D, Dunham I, Higgs DR, Gibbons RJ (2010) ATR-X idation. Neuron 42:961–972 syndrome protein targets tandem repeats and influences allele- Kourmouli N, Sun YM, van der Sar S, Singh PB, Brown JP (2005) specific expression in a size-dependent manner. Cell 143: Epigenetic regulation of mammalian pericentric heterochromatin 367–378 in vivo by HP1. Biochem Biophys Res Commun 337(3):901–907 Layman WS, McEwen DP, Beyer LA, Lalani SR, Fernbach SD, Oh E, Kraft M, Cirstea IC, Voss AK, Thomas T, Goehring I, Sheikh BN, Swaroop A, Hegg CC, Raphael Y, Martens JR, Martin DM Gordon L, Scott H, Smyth GK, Ahmadian MR, Trautmann U, (2009) Defects in neural stem cell proliferation and olfaction in Zenker M, Tartaglia M, Ekici A, Reis A, Do¨rr HG, Rauch A, Chd7 deficient mice indicate a mechanism for hyposmia in Thiel CT (2011) Disruption of the histone acetyltransferase human CHARGE syndrome. Hum Mol Genet 18(11):1909–1923 MYST4 leads to a Noonan syndrome-like phenotype and Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, hyperactivated MAPK signaling in humans and mice. J Clin Maystadt I, Dallapiccola B, Verellen-Dumoulin C (2012) Invest 121(9):3479–3491 Deletion of KDM6A, a histone demethylase interacting with Kramer JM, van Bokhoven H (2009) Genetic and epigenetic defects MLL2, in three patients with Kabuki syndrome. Am J Hum in mental retardation. Int J Biochem Cell Biol 41(1):96–107 Genet 90:119–124 Kramer JM, Kochinke K, Oortveld MA, Marks H, Kramer D, de Jong Lessard J, Wu JI, Ranish JA, Wan M, Winslow MM, Staahl BT, Wu EK, Asztalos Z, Westwood JT, Stunnenberg HG, Sokolowski H, Aebersold R, Graef IA, Crabtree GR (2007) An essential

123 380 Hum Genet (2013) 132:359–383

switch in subunit composition of a chromatin remodeling inherited case of brachydactyly mental retardation syndrome. complex during neural development. Neuron 55(2):201–215 Am J Med Genet A 158A(8):2015–2020 Lewis PW, Elsaesser SJ, Noh KM, Stadler SC, Allis CD (2010) Daxx Morrison AJ, Shen X (2009) Chromatin remodelling beyond is an H3.3-specific histone chaperone and cooperates with transcription: the INO80 and SWR1 complexes. Nat Rev Mol ATRX in replication-independent chromatin assembly at telo- Cell Biol 10(6):373–384 meres. Proc Natl Acad Sci USA 107(32):14075–14080 Muotri AR, Marchetto MC, Coufal NG, Oefner R, Yeo G, Nakashima Li H, Zhong X, Chau KF, Williams EC, Chang Q (2011) Loss of K, Gage FH (2010) L1 retrotransposition in neurons is modu- activity-induced phosphorylation of MeCP2 enhances synapto- lated by MeCP2. Nature 468(7322):443–446 genesis. LTP and spatial memory. Nat Neurosci 14(8): Murawska M, Brehm A (2011) CHD chromatin remodelers and the 1001–1008 transcription cycle. Transcription 2(6):244–253 Licht CL, Stevnsner T, Bohr VA (2003) Cockayne syndrome group B Na ES, Nelson ED, Kavalali ET, Monteggia LM (2012) The Impact cellular and biochemical functions. Am J Hum Genet 73: of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity. 1217–1239 Neuropsychopharmacology. doi:10.1038/npp.2012.116 Ling SC, Albuquerque CP, Han JS, Lagier-Tourenne C, Tokunaga S, Nagl NG Jr, Wang X, Patsialou A, Van Scoy M, Moran E (2007) Zhou H, Cleveland DW (2010) ALS-associated mutations in Distinct mammalian SWI/SNF chromatin remodeling complexes TDP-43 increase its stability and promote TDP-43 complexes with opposing roles in cell-cycle control. EMBO J 26(3): with FUS/TLS. Proc Natl Acad Sci USA 107(30):13318–13323 752–763 Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Nakamura Y, Tagawa K, Oka T, Sasabe T, Ito H, Shiwaku H, La Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N, Mandel G Spada AR, Okazawa H (2012) Ataxin-7 associates with micro- (2011) A role for glia in the progression of Rett’s syndrome. tubules and stabilizes the cytoskeletal network. Hum Mol Genet Nature 475(7357):497–500 21(5):1099–1110 Liu L, van Groen T, Kadish I, Tollefsbol TO (2009) DNA Nan X, Hou J, Maclean A, Nasir J, Lafuente MJ, Shu X, Kriaucionis methylation impacts on learning and memory in aging. Neuro- S, Bird A (2007) Interaction between chromatin proteins MECP2 biol Aging 30(4):549–560 and ATRX is disrupted by mutations that cause inherited mental Liu W, Tanasa B, Tyurina OV, Zhou TY, Gassmann R, Liu WT, Ohgi retardation. Proc Nat Acad Sci USA 104:2709–2714 KA, Benner C, Garcia-Bassets I, Aggarwal AK, Desai A, Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Dorrestein PC, Glass CK, Rosenfeld MG (2010) PHF8 mediates Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, histone H4 lysine 20 demethylation events involved in cell cycle McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman progression. Nature 466(7305):508–512 H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Lopez-Atalaya JP, Gervasini C, Mottadelli F, Spena S, Piccione M, Ubiquitinated TDP-43 in frontotemporal lobar degeneration and Scarano G, Selicorni A, Barco A, Larizza L (2012) Histone amyotrophic lateral sclerosis. Science 314(5796):130–133 acetylation deficits in lymphoblastoid cell lines from patients Newman JC, Bailey AD, Weiner AM (2006) Cockayne syndrome with Rubinstein-Taybi syndrome. J Med Genet 49(1):66–74 group B protein (CSB) plays a general role in chromatin Lu T, Jackson MW, Wang B, Yang M, Chance MR, Miyagi M, maintenance and remodeling. Proc Natl Acad Sci USA Gudkov AV, Stark GR (2010) Regulation of NF-kappaB by 103(25):9613–9618 NSD1/FBXL11-dependent reversible lysine methylation of p65. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Proc Natl Acad Sci USA 107(1):46–51 Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Macrae IJ, Zhou K, Li F, Repic A, Brooks AN, Cande WZ, Adams Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, PD, Doudna JA (2006) Structural basis for double-stranded RNA Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad processing by Dicer. Science 311(5758):195–198 MJ, Shendure J (2010) Exome sequencing identifies MLL2 Mayo S, Garin I, Monfort S, Rosello´ M, Orellana C, Oltra S, Zazo C, mutations as a cause of Kabuki syndrome. Nat Genet 42: de Naclares GP, Martı´nez F (2012) Hypomethylation of the 790–793 KCNQ1OT1 imprinting center of chromosome 11 associated to Nguyen MV, Du F, Felice CA, Shan X, Nigam A, Mandel G, Sotos-like features. J Hum Genet 57(2):153–156 Robinson JK, Ballas N (2012) MeCP2 Is Critical for Maintaining McMahon SJ, Pray-Grant MG, Schieltz D, Yates JR 3rd, Grant PA Mature Neuronal Networks and Global Brain Anatomy during (2005) Polyglutamine-expanded spinocerebellar ataxia-7 protein Late Stages of Postnatal Brain Development and in the Mature disrupts normal SAGA and SLIK histone acetyltransferase Adult Brain. J Neurosci 32(29):10021–10034 activity. Proc Natl Acad Sci USA 102(24):8478–8482 Nielsen AL, Jørgensen P, Lerouge T, Cervin˜o M, Chambon P, Losson McManus KJ, Hendzel MJ (2003) Quantitative analysis of CBP- and R (2004) Nizp1, a novel multitype zinc finger protein that P300-induced histone acetylations in vivo using native chroma- interacts with the NSD1 histone lysine methyltransferase through tin. Mol Cell Biol 23(21):7611–7627 a unique C2HR motif. Mol Cell Biol 24(12):5184–5196 Merson TD, Dixon MP, Collin C, Rietze RL, Bartlett PF, Thomas T, Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T (1981) Voss AK (2006) The transcriptional coactivator Querkopf Kabuki make-up syndrome: a syndrome of mental retardation, controls adult neurogenesis. J Neurosci 26(44):11359–11370 unusual facies, large and protruding ears, and postnatal growth Miska EA, Langley E, Wolf D, Karlsson C, Pines J, Kouzarides T deficiency. J Pediat 99:565–569 (2001) Differential localization of HDAC4 orchestrates muscle Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y (2002) differentiation. Nucleic Acids Res 29(16):3439–3447 A complex with chromatin modifiers that occupies E2F- and Monroy MA, Ruhl DD, Xu X, Granner DK, Yaciuk P, Chrivia JC Myc-responsive genes in G0 cells. Science 296(5570): (2001) Regulation of cAMP-responsive element-binding protein- 1132–1136 mediated transcription by the SNF2/SWI-related protein. Ogryzko VV, Schiltz RL, Russanova V, Howard BH, Nakatani Y SRCAP. J Biol Chem 276(44):40721–40726 (1996) The transcriptional coactivators p300 and CBP are Moretti P, Zoghbi HY (2006) MeCP2 dysfunction in Rett syndrome histone acetyltransferases. Cell 87:953–959 and related disorders. Curr Opin Genet Dev 16(3):276–281 Ounap K, Puusepp-Benazzouz H, Peters M, Vaher U, Rein R, Proos Morris B, Etoubleau C, Bourthoumieu S, Reynaud-Perrine S, Laroche A, Field M, Reimand T (2012) A novel c.2T [ C mutation of the C, Lebbar A, Yardin C, Elsea SH (2012) Dose dependent KDM5C/JARID1C gene in one large family with X-linked expression of HDAC4 causes variable expressivity in a novel intellectual disability. Eur J Med Genet 55(3):178–184

123 Hum Genet (2013) 132:359–383 381

Park JH, Park EJ, Lee HS, Kim SJ, Hur SK, Imbalzano AN, Kwon J Samaco RC, Nagarajan RP, Braunschweig D (2004) LaSalle JM (2006) Mammalian SWI/SNF complexes facilitate DNA double- (2004) Multiple pathways regulate MeCP2 expression in normal strand break repair by promoting gamma-H2AX induction. brain development and exhibit defects in autism-spectrum EMBO J 25(17):3986–3997 disorders. Hum Mol Genet 13(6):629–639 Pasillas MP, Shah M, Kamps MP (2011) NSD1 PHD domains bind Samaco RC, Hogart A, LaSalle JM (2005) Epigenetic overlap in methylated H3K4 and H3K9 using interactions disrupted by autism-spectrum neurodevelopmental disorders: MECP2 defi- point mutations in human Sotos syndrome. Hum Mutat ciency causes reduced expression of UBE3A and GABRB3. 32(3):292–298 Hum Mol Genet 14(4):483–492 Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno Sanlaville D, Etchevers HC, Gonzales M, Martinovic J, Cle´ment-Ziza M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ M, Delezoide AL, Aubry MC, Pelet A, Chemouny S, Cruaud C, (1995) Rubinstein-Taybi syndrome caused by mutations in the Audollent S, Esculpavit C, Goudefroye G, Ozilou C, Fredouille transcriptional co-activator CBP. Nature 376(6538):348–351 C, Joye N, Morichon-Delvallez N, Dumez Y, Weissenbach J, Picketts DJ, Higgs DR, Bachoo S, Blake DJ, Quarrell OW, Gibbons Munnich A, Amiel J, Encha-Razavi F, Lyonnet S, Vekemans M, RJ (1996) ATRX encodes a novel member of the SNF2 family of Attie´-Bitach T (2006) Phenotypic spectrum of CHARGE proteins: mutations point to a common mechanism underlying syndrome in fetuses with CHD7 truncating mutations correlates the ATR-X syndrome. Hum Molec Genet 5:1899–1907 with expression during human development. J Med Genet Portela A, Esteller M (2010) Epigenetic modifications and human 43:211–217 disease. Nat Biotechnol 28(10):1057–1068 Santen GW, Aten E, Sun Y, Almomani R, Gilissen C, Nielsen M, Qi HH, Sarkissian M, Hu GQ, Wang Z, Bhattacharjee A, Gordon DB, Kant SG, Snoeck IN, Peeters EA, Hilhorst-Hofstee Y, Wessels Gonzales M, Lan F, Ongusaha PP, Huarte M, Yaghi NK, Lim H, MW, den Hollander NS, Ruivenkamp CA, van Ommen GJ, Garcia BA, Brizuela L, Zhao K, Roberts TM, Shi Y (2010) Breuning MH, den Dunnen JT, van Haeringen A, Kriek M Histone H4K20/H3K9 demethylase PHF8 regulates zebrafish (2012) Mutations in SWI/SNF chromatin remodeling complex brain and craniofacial development. Nature 466(7305):503–507 gene ARID1B cause Coffin-Siris syndrome. Nat Genet Qiao Y, Liu X, Harvard C, Hildebrand MJ, Rajcan-Separovic E, 44:379–380 Holden JJ, Lewis ME (2008) Autism-associated familial mic- Santos-Rebouc¸as CB, Fintelman-Rodrigues N, Jensen LR, Kuss AW, rodeletion of Xp11.22. Clin Genet 74(2):134–144 Ribeiro MG, Campos M Jr, Santos JM, Pimentel MM (2011) A Rahman N (2005) Mechanisms predisposing to childhood overgrowth novel nonsense mutation in KDM5C/JARID1C gene causing and cancer. Curr Opin Genet Dev 15(3):227–233 intellectual disability, short stature and speech delay. Neurosci Rajan I, Savelieva KV, Ye GL, Wang CY, Malbari MM, Friddle C, Lett 498:67–71 Lanthorn TH, Zhang W (2009) Loss of the putative catalytic Schnetz MP, Bartels CF, Shastri K, Balasubramanian D, Zentner GE, domain of HDAC4 leads to reduced thermal nociception and Balaji R, Zhang X, Song L, Wang Z, Laframboise T, Crawford seizures while allowing normal bone development. PLoS ONE GE, Scacheri PC (2009) Genomic distribution of CHD7 on 4(8):e6612 chromatin tracks H3K4 methylation patterns. Genome Res Ravn K, Nielsen JB, Uldall P, Hansen FJ, Schwartz M (2003) No 19(4):590–601 correlation between phenotype and genotype in boys with a Scuto A, Kirschbaum M, Kowolik C, Kretzner L, Juhasz A, Atadja P, truncating MECP2 mutation. J Med Genet 40(1):e5 Pullarkat V, Bhatia R, Forman S, Yen Y, Jove R (2008) The Rayasam GV, Wendling O, Angrand PO, Mark M, Niederreither K, novel histone deacetylase inhibitor, LBH589, induces expression Song L, Lerouge T, Hager GL, Chambon P, Losson R (2003) of DNA damage response genes and apoptosis in Ph- acute NSD1 is essential for early post-implantation development and lymphoblastic leukemia cells. Blood 111(10):5093–5100 has a catalytically active SET domain. EMBO J 22(12): Seenundun S, Rampalli S, Liu QC, Aziz A, Palii C, Hong S, Blais A, 3153–3163 Brand M, Ge K, Dilworth FJ (2010) UTX mediates demethyl- Reardon W (2002) Genitopatellar syndrome: a recognizable pheno- ation of H3K27me3 at muscle-specific genes during myogenesis. type. Am J Med Genet 111:313–315 EMBO J 29(8):1401–1411 Reik W (2007) Stability and flexibility of epigenetic gene regulation Seo S, Richardson GA, Kroll KL (2005) The SWI/SNF chromatin in mammalian development. Nature 447(7143):425–432 remodeling protein Brg1 is required for vertebrate neurogenesis Reisman D, Glaros S, Thompson EA (2009) The SWI/SNF complex and mediates transactivation of Ngn and NeuroD. Development and cancer. Oncogene 28(14):1653–1668 132(1):105–115 Rio Frio T, Bahubeshi A, Kanellopoulou C, Hamel N, Niedziela M, Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Sabbaghian N, Pouchet C, Gilbert L, O’Brien PK, Serfas K, Noebels J, Armstrong D, Paylor R, Zoghbi H (2002) Mice with Broderick P, Houlston RS, Lesueur F, Bonora E, Muljo S, truncated MeCP2 recapitulate many Rett syndrome features and Schimke RN, Bouron-Dal Soglio D, Arseneau J, Schultz KA, display hyperacetylation of histone H3. Neuron 35:243–254 Priest JR, Nguyen VH, Harach HR, Livingston DM, Foulkes Shiohama A, Sasaki T, Noda S, Minoshima S, Shimizu N (2003) WD, Tischkowitz M (2011) DICER1 mutations in familial Molecular cloning and expression analysis of a novel gene multinodular goiter with and without ovarian Sertoli-Leydig cell DGCR8 located in the DiGeorge syndrome chromosomal region. tumors. JAMA 305:68–77 Biochem Biophys Res Commun 304:184–190 Roelfsema JH, White SJ, Ariyu¨rek Y, Bartholdi D, Niedrist D, Siderius LE, Hamel BC, van Bokhoven H, de Jager F, van den Papadia F, Bacino CA, den Dunnen JT, van Ommen GJ, Helm B, Kremer H, Heineman-de Boer JA, Ropers HH, Breuning MH, Hennekam RC, Peters DJ (2005) Genetic Mariman EC (1999) X-linked mental retardation associated heterogeneity in Rubinstein-Taybi syndrome: mutations in both with cleft lip/palate maps to Xp11.3-q21.3. Am J Med Genet the CBP and EP300 genes cause disease. Am J Hum Genet 85:216–220 76(4):572–580 Simpson MA, Deshpande C, Dafou D, Vissers LE, Woollard WJ, Ruhl DD, Jin J, Cai Y, Swanson S, Florens L, Washburn MP, Holder SE, Gillessen-Kaesbach G, Derks R, White SM, Cohen- Conaway RC, Conaway JW, Chrivia JC (2006) Purification of a Snuijf R, Kant SG, Hoefsloot LH, Reardon W, Brunner HG, human SRCAP complex that remodels chromatin by incorpo- Bongers EM, Trembath RC (2012) De novo mutations of the rating the histone variant H2A.Z into nucleosomes. Biochemistry gene encoding the histone acetyltransferase KAT6B cause 45:5671–5677 Genitopatellar syndrome. Am J Hum Genet 90(2):290–294

123 382 Hum Genet (2013) 132:359–383

Slupianek A, Yerrum S, Safadi FF, Monroy MA (2010) The CpG binding protein 2 (MeCP2). Nucleic Acids Res chromatin remodeling factor SRCAP modulates expression of 32(14):4100–4108 prostate specific antigen and cellular proliferation in prostate Van Esch H, Bauters M, Ignatius J, Jansen M, Raynaud M, Hollanders cancer cells. J Cell Physiol 224(2):369–375 K, Lugtenberg D, Bienvenu T, Jensen LR, Gecz J, Moraine C, Song J, Teplova M, Ishibe-Murakami S, Patel DJ (2012) Structure- Marynen P, Fryns JP, Froyen G (2005) Duplication of the based mechanistic insights into DNMT1-mediated maintenance MECP2 region is a frequent cause of severe mental retardation DNA methylation. Science 335(6069):709–712 and progressive neurological symptoms in males. Am J Hum Sopher BL, Ladd PD, Pineda VV, Libby RT, Sunkin SM, Hurley JB, Genet 77(3):442–453 Thienes CP, Gaasterland T, Filippova GN, La Spada AR (2011) Van Houdt JK, Nowakowska BA, Sousa SB, van Schaik BD, CTCF regulates ataxin-7 expression through promotion of a Seuntjens E, Avonce N, Sifrim A, Abdul-Rahman OA, van den convergently transcribed, antisense noncoding RNA. Neuron Boogaard MJ, Bottani A, Castori M, Cormier-Daire V, Deardorff 70:1071–1084 MA, Filges I, Fryer A, Fryns JP, Gana S, Garavelli L, Gillessen- Stark KL, Xu B, Bagchi A, Lai WS, Liu H, Hsu R, Wan X, Pavlidis P, Kaesbach G, Hall BD, Horn D, Huylebroeck D, Klapecki J, Mills AA, Karayiorgou M, Gogos JA (2008) Altered brain Krajewska-Walasek M, Kuechler A, Lines MA, Maas S, microRNA biogenesis contributes to phenotypic deficits in a Macdermot KD, McKee S, Magee A, de Man SA, Moreau Y, 22q11-deletion mouse model. Nat Genet 40:751–760 Morice-Picard F, Obersztyn E, Pilch J, Rosser E, Shannon N, Tahiliani M, Mei P, Fang R, Leonor T, Rutenberg M, Shimizu F, Li J, Stolte-Dijkstra I, Van Dijck P, Vilain C, Vogels A, Wakeling E, Rao A, Shi Y (2007) The histone H3K4 demethylase SMCX Wieczorek D, Wilson L, Zuffardi O, van Kampen AH, Devriendt links REST target genes to X-linked mental retardation. Nature K, Hennekam R, Vermeesch JR (2012) Heterozygous missense 447:601–605 mutations in SMARCA2 cause Nicolaides-Baraitser syndrome. Tao J, Hu K, Chang Q, Wu H, Sherman NE, Martinowich K, Klose Nat Genet 44:445–449 RJ, Schanen C, Jaenisch R, Wang W, Sun YE (2009) Vecsey CG, Hawk JD, Lattal KM, Stein JM, Fabian SA, Attner MA, Phosphorylation of MeCP2 at Serine 80 regulates its chromatin Cabrera SM, McDonough CB, Brindle PK, Abel T, Wood MA association and neurological function. Proc Natl Acad Sci USA (2007) Histone deacetylase inhibitors enhance memory and 106(12):4882–4887 synaptic plasticity via CREB: CBP-dependent transcriptional Tatton-Brown K, Rahman N (2007) Sotos syndrome. Eur J Hum activation. J Neurosci 27:6128–6140 Genet 15(3):264–271 Villard L (2007) MECP2 mutations in males. J Med Genet 44: Tatton-Brown K, Hanks S, Ruark E, Zachariou A, Duarte Sdel V, 417–423 Ramsay E, Snape K, Murray A, Perdeaux ER, Seal S, Loveday Viosca J, Lo´pez-Ayala JP, Olivares R, Eckner R, Barco A (2010) C, Banka S, Clericuzio C, Flinter F, Magee A, McConnell V, Syndromic features and mild cognitive impairment in mice with Patton M, Raith W, Rankin J, Splitt M, Strenger V, Taylor C, genetic reduction on p300 activity: differential contribution of Wheeler P, Temple KI, Cole T; Childhood Overgrowth Collab- p300 and CBP to Rubinstein-Taybi syndrome etiology. Neuro- oration, Douglas J, Rahman N (2011) Germline mutations in the biol Dis 37:186–194 oncogene EZH2 cause Weaver syndrome and increased human Wang J, Weaver IC, Gauthier-Fisher A, Wang H, He L, Yeomans J, height. Oncotarget 2(12):1127-1133 Wondisford F, Kaplan DR, Miller FD (2010) CBP histone Thomas T, Voss AK, Chowdhury K, Gruss P (2000) Querkopf, a acetyltransferase activity regulates embryonic neural differenti- MYST family histone acetyltransferase, is required for ation in the normal and Rubinstein-Taybi syndrome brain. Dev normal cerebral cortex development. Development 127(12): Cell 18(1):114–125 2537–2548 Watson P, Black G, Ramsden S, Barrow M, Super M, Kerr B, Tropea D, Giacometti E, Wilson NR, Beard C, McCurry C, Fu DD, Clayton-Smith J (2001) Angelman syndrome phenotype associ- Flannery R, Jaenisch R, Sur M (2009) Partial reversal of Rett ated with mutations in MECP2, a gene encoding a methyl CpG Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl binding protein. J Med Genet 38:224–228 Acad Sci USA106(6):2029-2034 Weaver DD, Graham CB, Thomas IT, Smith DW (1974) A new Tsai AC, Dossett CJ, Walton CS, Cramer AE, Eng PA, Nowakowska overgrowth syndrome with accelerated skeletal maturation, BA, Pursley AN, Stankiewicz P, Wiszniewska J, Cheung SW unusual facies, and camptodactyly. J Pediat 84:547–552 (2011) Exon deletions of the EP300 and CREBBP genes in two Wegorzewska I, Bell S, Cairns NJ, Miller TM, Baloh RH (2009) children with Rubinstein-Taybi syndrome detected by aCGH. TDP-43 mutant transgenic mice develop features of ALS and Europ J Hum Genet 19:43–49 frontotemporal lobar degeneration. Proc Natl Acad Sci USA Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, 106(44):18809–18814 Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink- Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Lindhout WM, van Bokhoven H, Philip N, Berry-Kravis EM, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Kini U, van Ravenswaaij-Arts CM, Delle Chiaie B, Innes AM, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Houge G, Kosonen T, Cremer K, Fannemel M, Stray-Pedersen Miyake N, Matsumoto N (2012) Mutations affecting components A, Reardon W, Ignatius J, Lachlan K, Mircher C, Helderman van of the SWI/SNF complex cause Coffin-Siris syndrome. Nat den Enden PT, Mastebroek M, Cohn-Hokke PE, Yntema HG, Genet 44:376-378 Drunat S, Kleefstra T (2012) Update on Kleefstra Syndrome. Urdinguio RG, Lopez-Serra L, Lopez-Nieva P, Alaminos M, Diaz- Mol Syndromol 2(3–5):202–212 Uriarte R, Fernandez AF, Esteller M (2008) Mecp2-null mice Williams SR, Aldred MA, Der Kaloustian VM, Halal F, Gowans G, provide new neuronal targets for Rett syndrome. PLoS ONE McLeod DR, Zondag S, Toriello HV, Magenis RE, Elsea SH 3(11):e3669 (2010) Haploinsufficiency of HDAC4 causes brachydactyly Urdinguio RG, Sanchez-Mut JV, Esteller M (2009) Epigenetic mental retardation syndrome, with brachydactyly type E, devel- mechanisms in neurological diseases: genes, syndromes, and opmental delays, and behavioral problems. Am J Hum Genet therapies. Lancet Neurol 8(11):1056–1072 87:219–228 Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC Winkelmann J, Lin L, Schormair B, Kornum BR, Faraco J, Plazzi G, (2004) Oxidative damage to methyl-CpG sequences inhibits the Melberg A, Cornelio F, Urban AE, Pizza F, Poli F, Grubert F, binding of the methyl-CpG binding domain (MBD) of methyl- Wieland T, Graf E, Hallmayer J, Strom TM, Mignot E (2012)

123 Hum Genet (2013) 132:359–383 383

Mutations in DNMT1 cause autosomal dominant cerebellar Yazdani M, Deogracias R, Guy J, Poot RA, Bird A, Barde YA (2010) ataxia, deafness and narcolepsy. Hum Mol Genet 21(10): Disease modeling using embryonic stem cells: MeCP2 regulates 2205–2210 nuclear size and RNA synthesis in neurons. Stem Cells Wolff D, Endele S, Azzarello-Burri S, Hoyer J, Zweier M, Schanze I, 30(10):2128–2139 Schmitt B, Rauch A, Reis A, Zweier C (2012) In-frame deletion Yehezkel S, Segev Y, Viegas-Pe´quignot E, Skorecki K, Selig S and missense mutations of the C-terminal helicase domain of (2008) Hypomethylation of subtelomeric regions in ICF syn- SMARCA2 in three patients with Nicolaides-Baraitser syn- drome is associated with abnormally short telomeres and drome. Molec Syndromol 2:237–244 enhanced transcription from telomeric regions. Hum Mol Genet Wong MM, Cox L, Chrivia J (2007) The chromatin remodeling 17(18):2776–2789 protein SRCAP is critical for deposition of the histone variant Yoneda Y, Saitsu H, Touyama M, Makita Y, Miyamoto A, Hamada H2A.Z at promoters. J Biol Chem 282:26132–26139 K, Kurotaki N, Tomita H, Nishiyama K, Tsurusaki Y, Doi H, Wong LH, McGhie JD, Sim M, Anderson MA, Ahn S, Hannan RD, Miyake N, Ogata K, Naritomi K, Matsumoto N (2012) Missense George AJ, Morgan KA, Mann JR, Choo KH (2010) ATRX mutations in the DNA-binding/dimerization domain of NFIX interacts with H3.3 in maintaining telomere structural integrity cause Sotos-like features. J Hum Genet 57(3):207-211 in pluripotent embryonic stem cells. Genome Res 20(3):351–360 Yoo SY, Pennesi ME, Weeber EJ, Xu B, Atkinson R, Chen S, Wyngaarden LA, Delgado-Olguin P, Su IH, Bruneau BG, Hopyan S Armstrong DL, Wu SM, Sweatt JD, Zoghbi HY (2003) SCA7 (2011) Ezh2 regulates anteroposterior axis specification and knockin mice model human SCA7 and reveal gradual accumu- proximodistal axis elongation in the developing limb. Develop- lation of mutant ataxin-7 in neurons and abnormalities in short- ment 138(17):3759–3767 term plasticity. Neuron 37(3):383–401 Xie W, Ling T, Zhou Y, Feng W, Zhu Q, Stunnenberg HG, Grummt I, Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose Tao W (2012) The chromatin remodeling complex NuRD MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY establishes the poised state of rRNA genes characterized by (2005) Regulation of RNA splicing by the methylation-depen- bivalent histone modifications and altered nucleosome positions. dent transcriptional repressor methyl-CpG binding protein 2. Proc Natl Acad Sci USA 109(21):8161–8166 Proc Natl Acad Sci USA102(49):17551-17558 Xu GL, Bestor TH, Bourc’his D, Hsieh CL, Tommerup N, Bugge M, Yu L, Wang Y, Huang S, Wang J, Deng Z, Zhang Q, Wu W, Zhang Hulten M, Qu X, Russo JJ, Viegas-Pe´quignot E (1999) X, Liu Z, Gong W, Chen Z (2010) Structural insights into a Chromosome instability and immunodeficiency syndrome novel histone demethylase PHF8. Cell Res 20(2):166–173 caused by mutations in a DNA methyltransferase gene. Nature Yuan X, Feng W, Imhof A, Grummt I, Zhou Y (2007) Activation of 402:187–191 RNA polymerase I transcription by cockayne syndrome group B Xu J, Deng X, Disteche CM (2008) Sex-specific expression of the protein and histone methyltransferase G9a. Mol Cell X-linked histone demethylase gene Jarid1c in brain. PLoS ONE 27(4):585–595 3(7):e2553 Zachariah RM, Rastegar M (2012) Linking epigenetics to human Yang X, Noushmehr H, Han H, Andreu-Vieyra C, Liang G, Jones PA disease and Rett syndrome: the emerging novel and challenging (2012) Gene reactivation by 5-aza-20-deoxycytidine-induced concepts in MeCP2 research. Neural Plast 2012:415825 demethylation requires SRCAP-mediated H2A.Z insertion to Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, Chen WG, establish nucleosome depleted regions. PLoS Genet 8(3):e1002604 Lin Y, Savner E, Griffith EC, Hu L, Steen JA, Weitz CJ, Yasui DH, Peddada S, Bieda MC, Vallero RO, Hogart A, Nagarajan Greenberg ME (2006) Brain-specific phosphorylation of MeCP2 RP, Thatcher KN, Farnham PJ, Lasalle JM (2007) Integrated regulates activity-dependent Bdnf transcription, dendritic epigenomic analyses of neuronal MeCP2 reveal a role for long- growth, and spine maturation. Neuron 52(2):255–269 range interaction with active genes. Proc Natl Acad Sci USA 104(49):19416–19421

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