INSIGHT REVIEW NATURE Vol 447 24 May 2007 Figure 3 Phenotypic plasticity and the epigenetics Rett syndrome of human disease and ageing. A common feature of epigenetic lesions in human disease is that they affect Subo goma Johe Gene A a cells ability to change its phenotype disorders such as Rett syndrome, a defect in the lf impedes normal development. DNA methylation(brown circles on he dNA) proceeds normally but is not recognize he absence of the MeCP2-methylatio Gene A er Gene A interacting protein(large red oval). This leads t failure to completely silence genes appropriately during development(dashed arrow). b, Cancer involves nany epigenetic lesions that could affect a pluripotent Cancer ading to an incorrect distribution of differentiated cell lineages(indicated by the bivalent euchromatin ns shown in the upper left and activation of gene B after differentiation(lower left panel). Examples of epigenetic lesions found in cancer Gene B include changes caused by increased expression of MLLI in leukaemia representing HOX genes), leading to aberrant HOX expression in differentiated cancer lineages(lower right 她颜m In cancer expression of EZH2 (upp g uppressor genes), leading to aberrant silencing of these genes in differentiated cancer lineages (lower right panel). c, Ageing involves a loss of the normal plasticity Gene B Gene b of to internal and external environmenta signals. The epigenome could have an important role such signals. For example, a gene(at this point Ageing pathetically) showing increased H3K9-methylatie red circles on nucleos or dna ENVIRONM MENT ENVIRONMENT methylation(brown circles on DNA), might be relatively refractory to environmentally induced activation(lowe Gene a right panel)than if the gene had not undergone age- Gene A Gene A ormally silent allele of an imprinted growth-promoting gene, or aber- development. For example, in the fungus Neurospora DNa methylation rant silencing of the normally expressed copy of an imprinted tumour depends on H3K9 methylation", and in mice DNA methylation of suppressor gene, such as the still unidentified locus on 1lp15(ref. 31). homeobox(Hox) genes depends on a full length Mll (myeloid/lymph Subsequently, LOI of IGF2 has been found to be common in lung can- oid or mixed-lineage leukaemia) gene. DNMTI interacts with the cer", breast cancer ovarian cancer and glioma" LOI of other genes H3K9 methyltransferases G9a and SUV39H1, which are needed for ARHI in breast cancer DLKI/GTL2 in pheochromocytoma, normal replication-dependent DNA methylation". Some chromosomal stoma and wilms tumour, and PEGI(also known as MEST) rearrangements and, less commonly, mutations in cancer act by caus ing widespread chromatin disruption. MLLI, which is rearranged and activated in acute lymphoblastic leukaemia, methylates H3K4 to activate Chromatin and cancer ne expression and interacts with integrase integrator 1(INII)in the It has become increasingly clear that in cancer chromatin modifica- SWI/SNF chromatin remodelling complex". INII is mutated in rhab- tions are at least as widespread and important as alterations in dNa doid tumour, a deadly soft-tissue malignancy. Sotos syndrome, which ethylation. For example, overexpression of the polycomb group protein is characterized by tissue overgrowth, leukaemia and wilms tumour, is EZH2, a H3 lysine-27(H3K27)histone methyltransferase, is found in caused by mutations in NSDI, an H3K36/H4K20 methyltransf metastatic prostate cancer and may lead to widespread transcriptional Thus, a strong argument can be made for chromatin modifications driv- repression"(Fig 3). Generalized loss of H4 acetylated Lys-16 (H4K16ac) ing epigenetic disruptions during cancer developmen and trimethylated Lys-20(H4K20me3)is found in lymphoma and olorectal cancer, which could also lead to transcriptional silencing The argument for causality Fig 3). It is not surprising that both DNA methylation and histone One problem with the idea that alterations in DNA methylation under modification are altered in cancer, given their interdependence in normal lie cancer is that no mutations in either the methylation modification or 436 @2007 Nature Publishing Groupnormally silent allele of an imprinted growth-promoting gene, or aber￾rant silencing of the normally expressed copy of an imprinted tumour suppressor gene, such as the still unidentified locus on 11p15 (ref. 31). Subsequently, LOI of IGF2 has been found to be common in lung can￾cer32, breast cancer33, ovarian cancer34 and glioma35. LOI of other genes include ARHI in breast cancer36, DLK1/GTL2 in pheochromocytoma, neuroblastoma and Wilms’ tumour37, and PEG1 (also known as MEST) in breast cancer38. Chromatin and cancer It has become increasingly clear that in cancer chromatin modifica￾tions are at least as widespread and important as alterations in DNA methylation. For example, overexpression of the polycomb group protein EZH2, a H3 lysine-27 (H3K27) histone methyltransferase, is found in metastatic prostate cancer and may lead to widespread transcriptional repression39 (Fig. 3). Generalized loss of H4 acetylated Lys-16 (H4K16ac) and trimethylated Lys-20 (H4K20me3) is found in lymphoma and colorectal cancer, which could also lead to transcriptional silencing40 (Fig. 3). It is not surprising that both DNA methylation and histone modification are altered in cancer, given their interdependence in normal development. For example, in the fungus Neurospora DNA methylation depends on H3K9 methylation41, and in mice DNA methylation of homeobox (Hox) genes depends on a full length Mll (myeloid/lymph￾oid or mixed-lineage leukaemia) gene42. DNMT1 interacts with the H3K9 methyltransferases G9a and SUV39H1, which are needed for normal replication-dependent DNA methylation43. Some chromosomal rearrangements and, less commonly, mutations in cancer act by caus￾ing widespread chromatin disruption. MLL1, which is rearranged and activated in acute lymphoblastic leukaemia, methylates H3K4 to activate gene expression and interacts with integrase integrator 1 (INI1) in the SWI/SNF chromatin remodelling complex44. INI1 is mutated in rhab￾doid tumour, a deadly soft-tissue malignancy45. Sotos syndrome, which is characterized by tissue overgrowth, leukaemia and Wilms’ tumour, is caused by mutations in NSD1, an H3K36/H4K20 methyltransferase46. Thus, a strong argument can be made for chromatin modifications driv￾ing epigenetic disruptions during cancer development. The argument for causality One problem with the idea that alterations in DNA methylation under￾lie cancer is that no mutations in either the methylation modification or Gene A Gene A Gene A Rett syndrome Cancer Gene A Gene A Gene B Gene A Gene A Normal Disease and ageing Gene B Gene A Gene A Gene B a b c Gene B Gene A Gene A Gene A ENVIRONMENT Ageing ENVIRONMENT Figure 3 | Phenotypic plasticity and the epigenetics of human disease and ageing. A common feature of epigenetic lesions in human disease is that they affect a cell’s ability to change its phenotype. a, In monogenic disorders such as Rett syndrome, a defect in the normal epigenetic apparatus itself impedes normal development. DNA methylation (brown circles on the DNA) proceeds normally but is not recognized owing to the absence of the MeCP2-methylation￾interacting protein (large red oval). This leads to failure to completely silence genes appropriately during development (dashed arrow). b, Cancer involves many epigenetic lesions that could affect a pluripotent programme in tissue-specific stem cells, possibly leading to an incorrect distribution of differentiated cell lineages (indicated by the bivalent euchromatin and heterochromatin proteins shown in the upper left panel) and normal tissue-specific silencing of gene A and activation of gene B after differentiation (lower left panel). Examples of epigenetic lesions found in cancer include changes in chromatin proteins in stem cells caused by increased expression of MLL1 in leukaemia (upper right panel, green complex above gene A representing HOX genes), leading to aberrant HOX expression in differentiated cancer lineages (lower right panel). Another epigenetic lesion found in cancer is increased expression of EZH2 (upper right panel, red complex above gene B, representing diverse tumour suppressor genes), leading to aberrant silencing of these genes in differentiated cancer lineages (lower right panel). c, Ageing involves a loss of the normal plasticity of response to internal and external environmental signals. The epigenome could have an important role in ageing if the aged epigenome is less responsive to such signals. For example, a gene (at this point hypothetically) showing increased H3K9-methylation (upper right panel, red circles on nucleosomes) or DNA methylation (brown circles on DNA), might be relatively refractory to environmentally induced activation (lower right panel) than if the gene had not undergone age￾dependent epigenetic change (left panels). 436 INSIGHT REVIEW NATURE|Vol 447|24 May 2007 ￾