INSIGHT REVIEW NATURE Vol 447 24 May 2007 pseudohypoparathyroidism type IA (PHPIA). Albright hereditary system development as well as developmental dysmorphology, which steodystrophy is characterized by short stature and ectopic calcifica- could involve failure of heterochromatin formation and might result tions, and caused by mutational inactivation of guanine nucleotide regu- from DNMT3B having a role in immunoglobulin gene silencing and latory protein(encoded by GNASI) PHPIA is a more severe phenotype reactivation f multiple hormone resistance caused by tissue-specific differential A striking example of developmental disruption caused by mutations imprinting of splice variants of the same gene. It is unlikely that this in a chromatin factor gene is alpha-thalassaemia/mental retardation, omplex pattern of imprinting would have been understood without X-linked(ATRX) syndrome, the gene for which is a helicase involved concomitant clinical studies in chromatin remodelling Mutations lead to defects in psychomotor, urogenital and haematopoietic development, with maturational defects Single-gene disorders of the epigenetic machinery in erythroid precursors resembling those of alpha-thalassaemia The other class of monogenic epigenetic disease involves genes that Rubinstein-Taybi syndrome involves the CREb(cyclic-AMP respon ncode comphese genes causes developmental disorders. For example, acetyltransferase activity, and mutations in CBP lead to skeletal and nents of the machinery that regulates the epigenome. sive-element-binding protein )-binding protein CBP, which has histone lutation of Rett syndrome involves mutations of the methyl CpG-binding protein 2 cardiac malformations, as well as neurodevelopmental malformations MeCP2)gene, which encodes a protein that binds to methylated dNa and loss of neural plasticity A common theme of these disorders is that sequences In Rett syndrome, DNA methylation proceeds normally mutations in epigenome regulators cause developmental disruption and but epigenetic silencing is impaired because of a failure to properly often cause ph henotypic changes in multiple organ systems recognize this mark(Fig 3). What is striking about the phenotype of this disorder is that prenatal and early infant development is normal, DNA methylation in cancer and erosion of neurodevelopmental milestones is not seen until later Cancer is commonly characterized as showing global hypomethylation childhood and site-specific gene hypermethylation, but a more accurate description Epigenetically disrupted development can occur in various biological is that cancer involves both global and gene-specific hypomethylation pathways or systems. Immunodeficiency/centromeric instability/facial and hypermethylation, as well as widespread chromatin modifications anomalies(ICF)syndrome, for example, affects the immune system (Fig 3). The first epigenetic change described in tumours was gene and involves mutations of the DNA methyltransferase gene DNMT3B, hypomethylation, and we now know that many growth-promoting ich is responsible for de novo DNA methylation during develop- genes are activated through hypomethylation in tumours, including ment. Patients wih ICF syndrome show failure of normal immune HRAS, cyclin D2 and maspin in gastric cancer, carbonic anhydrase IXin a normal b Epigenetic lesions Figure 1 The nature of epigenetic lesions. Although the nature of switch its epigenotype through the silencing of normally active genes or netic lesions is well understood ctivation of lly silent genes, with the attendant changes in DNA difficult to define. Here we depict known and possible defects in the pigenome that could lead to disease. a, X is a transcriptionally active the epigenetic lesion could include a change in the number or density ne with sparse DNA methylation(brown circles), an open chromatin of heterochromatin proteins in gene X(such as EZH2 in cancer)or tructure, interaction with euchromatin proteins(green prote euchromatic proteins in gene Y (such as trithorax in leukaemia). There complex)and histone modifications such as H3K9 acetylation and H3K4 may also be an abnormally dense pattern of methylation in gene promoters thylation(green circles ). Y is a transcriptionally silent gene with shown in gene X), and an overall reduction in DNA methylate dense DNA methylation, a closed chromatin structure, interaction with in cancer. The insets show that the higher-order heterochromatin proteins(red protein complex)and histone modifications configuratio be altered, although such structures are currently only uch as H3K27 methylation(pink circles). b, The abnormal cell could beginning to be understood. @2007 Nature Publishing Grouppseudohypoparathyroidism type IA (PHPIA). Albright hereditary osteodystrophy is characterized by short stature and ectopic calcifica￾tions, and caused by mutational inactivation of guanine nucleotide regu￾latory protein (encoded by GNAS1). PHPIA is a more severe phenotype of multiple hormone resistance caused by tissue-specific differential imprinting of splice variants of the same gene8 . It is unlikely that this complex pattern of imprinting would have been understood without concomitant clinical studies. Single-gene disorders of the epigenetic machinery The other class of monogenic epigenetic disease involves genes that encode components of the machinery that regulates the epigenome. Mutation of these genes causes developmental disorders. For example, Rett syndrome involves mutations of the methyl CpG-binding protein 2 (MeCP2) gene, which encodes a protein that binds to methylated DNA sequences9 . In Rett syndrome, DNA methylation proceeds normally but epigenetic silencing is impaired because of a failure to properly recognize this mark10 (Fig. 3). What is striking about the phenotype of this disorder is that prenatal and early infant development is normal, and erosion of neurodevelopmental milestones is not seen until later childhood. Epigenetically disrupted development can occur in various biological pathways or systems. Immunodeficiency/centromeric instability/facial anomalies (ICF) syndrome, for example, affects the immune system and involves mutations of the DNA methyltransferase gene DNMT3B, which is responsible for de novo DNA methylation during develop￾ment11. Patients wih ICF syndrome show failure of normal immune system development as well as developmental dysmorphology, which could involve failure of heterochromatin formation and might result from DNMT3B having a role in immunoglobulin gene silencing and reactivation12. A striking example of developmental disruption caused by mutations in a chromatin factor gene is alpha-thalassaemia/mental retardation, X-linked (ATRX) syndrome, the gene for which is a helicase involved in chromatin remodelling. Mutations lead to defects in psychomotor, urogenital and haematopoietic development, with maturational defects in erythroid precursors resembling those of alpha-thalassaemia13. Rubinstein–Taybi syndrome involves the CREB (cyclic-AMP respon￾sive-element-binding protein)-binding protein CBP, which has histone acetyltransferase activity, and mutations in CBP lead to skeletal and cardiac malformations, as well as neurodevelopmental malformations and loss of neural plasticity14. A common theme of these disorders is that mutations in epigenome regulators cause developmental disruption and often cause phenotypic changes in multiple organ systems. DNA methylation in cancer Cancer is commonly characterized as showing global hypomethylation and site-specific gene hypermethylation, but a more accurate description is that cancer involves both global and gene-specific hypomethylation and hypermethylation, as well as widespread chromatin modifications (Fig. 3). The first epigenetic change described in tumours was gene hypomethylation15, and we now know that many growth-promoting genes are activated through hypomethylation in tumours, including HRAS, cyclin D2 and maspin in gastric cancer, carbonic anhydrase IXin Gene X Gene Y Gene X Gene Y a Normal b Epigenetic lesions Figure 1 | The nature of epigenetic lesions. Although the nature of genetic lesions is well understood, epigenetic lesions have been more difficult to define. Here we depict known and possible defects in the epigenome that could lead to disease. a, X is a transcriptionally active gene with sparse DNA methylation (brown circles), an open chromatin structure, interaction with euchromatin proteins (green protein complex) and histone modifications such as H3K9 acetylation and H3K4 methylation (green circles). Y is a transcriptionally silent gene with dense DNA methylation, a closed chromatin structure, interaction with heterochromatin proteins (red protein complex) and histone modifications such as H3K27 methylation (pink circles). b, The abnormal cell could switch its epigenotype through the silencing of normally active genes or activation of normally silent genes, with the attendant changes in DNA methylation, histone modification and chromatin proteins. In addition, the epigenetic lesion could include a change in the number or density of heterochromatin proteins in gene X (such as EZH2 in cancer) or euchromatic proteins in gene Y (such as trithorax in leukaemia). There may also be an abnormally dense pattern of methylation in gene promoters (shown in gene X), and an overall reduction in DNA methylation (shown in gene Y) in cancer. The insets show that the higher-order loop configuration may be altered, although such structures are currently only beginning to be understood. 434 INSIGHT REVIEW NATURE|Vol 447|24 May 2007 ￾