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Genetic Syndromes Caused by Mutations in Epigenetic Genes

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Genetic Syndromes Caused by Mutations in Epigenetic Genes 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 Á 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
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