The complexity of epigenetic diseases

Journal of Pathology

Volumn 238, Issue 2, 2016, Pages 333-344

  Brazel, Ailbhe Jane ^a   Vernimmen, Douglas ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

cancer; chromatin; enhancer; epigenetics; leukaemia; mutations

Indexed keywords

CPG OLIGODEOXYNUCLEOTIDE; CYTOSINE; DNA; HISTONE H3; TRANSCRIPTION FACTOR EZH2;

BREAST CANCER; CANCER GENETICS; COLON CANCER; DNA METHYLATION; DNA MODIFICATION; ENHANCER REGION; EPIGENETICS; GAIN OF FUNCTION MUTATION; GENE; GENE DELETION; GENE EXPRESSION; GENETIC ASSOCIATION; GENETIC DISORDER; GENETIC REGULATION; GENETIC TRANSCRIPTION; GENETIC VARIABILITY; HISTONE MODIFICATION; HUMAN; LOSS OF FUNCTION MUTATION; MOLECULAR PATHOLOGY; PRIORITY JOURNAL; PROMOTER REGION; PROSTATE CANCER; REGULATOR GENE; REVIEW; ANIMAL; BIOLOGICAL MODEL; GENE EXPRESSION REGULATION; GENETIC EPIGENESIS; GENETICS; GENOME-WIDE ASSOCIATION STUDY; MUTATION; NEOPLASM; PROCEDURES; SINGLE NUCLEOTIDE POLYMORPHISM;

ANIMALS; DNA, NEOPLASM; ENHANCER ELEMENTS, GENETIC; EPIGENESIS, GENETIC; EPIGENOMICS; GENE EXPRESSION REGULATION, NEOPLASTIC; GENETIC DISEASES, INBORN; GENOME-WIDE ASSOCIATION STUDY; HUMANS; MODELS, GENETIC; MUTATION; NEOPLASMS; POLYMORPHISM, SINGLE NUCLEOTIDE;

EID: 84951317307     PISSN: 00223417     EISSN: 10969896     Source Type: Journal    
DOI: 10.1002/path.4647     Document Type: Review

References (180)

1. Slack JM,. Conrad Hal Waddington: the last Renaissance biologist? Nature Rev Genet 2002; 3: 889-895.
2. Goldberg AD, Allis CD, Bernstein E,. Epigenetics: a landscape takes shape. Cell 2007; 128: 635-638.
3. Kim TK, Shiekhattar R,. Architectural and functional commonalities between enhancers and promoters. Cell 2015; 162: 948-959.
4. Andersson R, Sandelin A, Danko CG,. A unified architecture of transcriptional regulatory elements. Trends Genet 2015; 31: 426-433.
5. Smith E, Shilatifard A,. Enhancer biology and enhanceropathies. Nature Struct Mol Biol 2014; 21: 210-219.
6. Vernimmen D., Uncovering enhancer functions using the alpha-globin locus. PLoS Genet 2014; 10: e1004668.
7. Tan M, Luo H, Lee S, et al., Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 2011; 146: 1016-1028.
8. Dawson MA, Kouzarides T,. Cancer epigenetics: from mechanism to therapy. Cell 2012; 150: 12-27.
9. Breiling A, Lyko F,. Epigenetic regulatory functions of DNA modifications: 5-methylcytosine and beyond. Epigenetics Chromatin 2015; 8: 24.
10. Tarakhovsky A., Tools and landscapes of epigenetics. Nature Immunol 2010; 11: 565-568.
11. Maire CL, Ligon KL,. Molecular pathologic diagnosis of epidermal growth factor receptor. Neuro Oncol 2014; 16 (Suppl 8): viii1-6.
12. Saadatpour A, Guo G, Orkin SH, et al., Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis. Genome Biol 2014; 15: 525.
13. Gawad C, Koh W, Quake SR,. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc Natl Acad Sci U S A 2014; 111: 17947-17952.
14. Paguirigan AL, Smith J, Meshinchi S, et al., Single-cell genotyping demonstrates complex clonal diversity in acute myeloid leukemia. Sci Transl Med 2015; 7:281re282.
15. Armstrong SA, Staunton JE, Silverman LB, et al., MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nature Genet 2002; 30: 41-47.
16. D'Haene B, Attanasio C, Beysen D, et al., Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening. PLoS Genet 2009; 5: e1000522.
17. Naranjo S, Voesenek K, de la Calle-Mustienes E, et al., Multiple enhancers located in a 1-Mb region upstream of POU3F4 promote expression during inner ear development and may be required for hearing. Hum Genet 2010; 128: 411-419.
18. Balemans W, Patel N, Ebeling M, et al., Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 2002; 39: 91-97.
19. Loots GG, Kneissel M, Keller H, et al., Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 2005; 15: 928-935.
20. Bondurand N, Fouquet V, Baral V, et al., Alu-mediated deletion of SOX10 regulatory elements in Waardenburg syndrome type 4. Eur J Hum Genet 2012; 20: 990-994.
21. Lecerf L, Kavo A, Ruiz-Ferrer M, et al., An impairment of long distance SOX10 regulatory elements underlies isolated Hirschsprung disease. Hum Mutat 2014; 35: 303-307.
22. Emison ES, McCallion AS, Kashuk CS, et al., A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 2005; 434: 857-863.
23. Emison ES, Garcia-Barcelo M, Grice EA, et al., Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. Am J Hum Genet 2010; 87: 60-74.
24. Lettice LA, Heaney SJ, Purdie LA, et al., A long-range Shh enhancer regulates expression in the developing limb and fin and is associated with preaxial polydactyly. Hum Mol Genet 2003; 12: 1725-1735.
25. Lettice LA, Hill AE, Devenney PS, et al., Point mutations in a distant sonic hedgehog cis-regulator generate a variable regulatory output responsible for preaxial polydactyly. Hum Mol Genet 2008; 17: 978-985.
26. Anderson E, Peluso S, Lettice LA, et al., Human limb abnormalities caused by disruption of hedgehog signaling. Trends Genet 2012; 28: 364-373.
27. Hindorff LA, Sethupathy P, Junkins HA, et al., Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci U S A 2009; 106: 9362-9367.
28. Manolio TA,. Genomewide association studies and assessment of the risk of disease. N Engl J Med 2010; 363: 166-176.
29. Ahmadiyeh N, Pomerantz MM, Grisanzio C, et al., 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 2010; 107: 9742-9746.
30. Jia L, Landan G, Pomerantz M, et al., Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 2009; 5: e1000597.
31. Sahu B, Laakso M, Ovaska K, et al., Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 2011; 30: 3962-3976.
32. de Wit E, de Laat W,. A decade of 3C technologies: insights into nuclear organization. Genes Dev 2012; 26: 11-24.
33. Tuupanen S, Turunen M, Lehtonen R, et al., The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nature Genet 2009; 41: 885-890.
34. Pomerantz MM, Ahmadiyeh N, Jia L, et al., The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nature Genet 2009; 41: 882-884.
35. Meyer KB, Maia AT, O'Reilly M, et al. A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. PLoS Genet 2011; 7: e1002165.
36. Yochum GS,. Multiple Wnt/ss-catenin responsive enhancers align with the MYC promoter through long-range chromatin loops. PLoS One 2011; 6: e18966.
37. Du M, Yuan T, Schilter KF, et al., Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome. Hum Mol Genet 2014; 24: 154-166.
38. Waszak SM, Delaneau O, Gschwind AR, et al., Population variation and genetic control of modular chromatin architecture in humans. Cell 2015; 162: 1039-1050.
39. Grubert F, Zaugg JB, Kasowski M, et al., Genetic control of chromatin states in humans involves local and distal chromosomal interactions. Cell 2015; 162: 1051-1065.
40. Heyn H, Carmona FJ, Gomez A, et al., DNA methylation profiling in breast cancer discordant identical twins identifies DOK7 as novel epigenetic biomarker. Carcinogenesis 2013; 34: 102-108.
41. Mohammad HP, Smitheman KN, Kamat CD, et al. A DNA hypomethylation signature predicts antitumor activity of LSD1 inhibitors in SCLC. Cancer Cell 2015; 28: 57-69.
42. Stone A, Zotenko E, Locke WJ, et al., DNA methylation of oestrogen-regulated enhancers defines endocrine sensitivity in breast cancer. Nature Commun 2015; 6: 7758.
43. De Gobbi M, Viprakasit V, Hughes JR, et al., A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter. Science 2006; 312: 1215-1217.
44. Trynka G, Sandor C, Han B, et al., Chromatin marks identify critical cell types for fine mapping complex trait variants. Nature Genet 2013; 45: 124-130.
45. Rivenbark AG, Stolzenburg S, Beltran AS, et al., Epigenetic reprogramming of cancer cells via targeted DNA methylation. Epigenetics 2012; 7: 350-360.
46. Teschendorff AE, Menon U, Gentry-Maharaj A, et al., An epigenetic signature in peripheral blood predicts active ovarian cancer. PLoS One 2009; 4: e8274.
47. Figueroa ME, Lugthart S, Li Y, et al., DNA methylation signatures identify biologically distinct subtypes in acute myeloid leukemia. Cancer Cell 2010; 17: 13-27.
48. Irizarry RA, Ladd-Acosta C, Wen B, et al., The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nature Genet 2009; 41: 178-186.
49. Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O, et al., Epigenomic enhancer profiling defines a signature of colon cancer. Science 2012; 336: 736-739.
50. Rakyan VK, Down TA, Balding DJ, et al., Epigenome-wide association studies for common human diseases. Nature Rev Genet 2011; 12: 529-541.
51. Liu Y, Aryee MJ, Padyukov L, et al., Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnol 2013; 31: 142-147.
52. Breitling LP, Yang R, Korn B, et al., Tobacco-smoking-related differential DNA methylation: 27 K discovery and replication. Am J Hum Genet 2011; 88: 450-457.
53. Shenker NS, Polidoro S, van Veldhoven K, et al., Epigenome-wide association study in the European Prospective Investigation into Cancer and Nutrition (EPIC-Turin) identifies novel genetic loci associated with smoking. Hum Mol Genet 2013; 22: 843-851.
54. Michels KB, Binder AM, Dedeurwaerder S, et al., Recommendations for the design and analysis of epigenome-wide association studies. Nature Methods 2013; 10: 949-955.
55. Zou J, Lippert C, Heckerman D, et al., Epigenome-wide association studies without the need for cell-type composition. Nature Methods 2014; 11: 309-311.
56. Smallwood SA, Lee HJ, Angermueller C, et al., Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nature Methods 2014; 11: 817-820.
57. Johnson TB, Coghill RD,. Researches on pyrimidines. C111. The discovery of 5-methyl-cytosine in tuberculinic acid, the nucleic acid of the tubercle bacillus. J Am Chem Soc 1925; 47: 7.
58. Deaton AM, Bird A,. CpG islands and the regulation of transcription. Genes Dev 2011; 25: 1010-1022.
59. Glastad KM, Hunt BG, Yi SV, et al., DNA methylation in insects: on the brink of the epigenomic era. Insect Mol Biol 2011; 20: 553-565.
60. Roberts SA, Gordenin DA,. Hypermutation in human cancer genomes: footprints and mechanisms. Nature Rev Cancer 2014; 14: 786-800.
61. Matsuo K, Clay O, Takahashi T, et al., Evidence for erosion of mouse CpG islands during mammalian evolution. Somat Cell Mol Genet 1993; 19: 543-555.
62. Antequera F, Bird A,. Number of CpG islands and genes in human and mouse. Proc Natl Acad Sci U S A 1993; 90: 11995-11999.
63. Wallace HA, Marques-Kranc F, Richardson M, et al., Manipulating the mouse genome to engineer precise functional syntenic replacements with human sequence. Cell 2007; 128: 197-209.
64. Yang L, Rau R, Goodell MA,. DNMT3A in haematological malignancies. Nature Rev Cancer 2015; 15: 152-165.
65. Pellagatti A, Boultwood J,. The molecular pathogenesis of the myelodysplastic syndromes. Eur J Haematol 2015; 95: 3-15.
66. Ley TJ, Ding L, Walter MJ, et al., DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424-2433.
67. Beurlet S, Chomienne C, Padua RA,. Engineering mouse models with myelodysplastic syndrome human candidate genes; how relevant are they? Haematologica 2012; 98: 10-22.
68. Holz-Schietinger C, Matje DM, Reich NO,. Mutations in DNA methyltransferase (DNMT3A) observed in acute myeloid leukemia patients disrupt processive methylation. J Biol Chem 2012; 287: 30941-30951.
69. Kim SJ, Zhao H, Hardikar S, et al., A DNMT3A mutation common in AML exhibits dominant-negative effects in murine ES cells. Blood 2013; 122: 4086-4089.
70. Wu H, Zhang Y,. Mechanisms and functions of Tet protein-mediated 5-methylcytosine oxidation. Genes Dev 2011; 25: 2436-2452.
71. Schubeler D., Function and information content of DNA methylation. Nature 2015; 517: 321-326.
72. Margueron R, Justin N, Ohno K, et al., Role of the polycomb protein EED in the propagation of repressive histone marks. Nature 2009; 461: 762-767.
73. Agger K, Christensen J, Cloos PA, et al., The emerging functions of histone demethylases. Curr Opin Genet Dev 2008; 18: 159-168.
74. Walport LJ, Hopkinson RJ, Vollmar M, et al., Human UTY(KDM6C) is a male-specific N-methyl lysyl demethylase. J Biol Chem 2014; 289: 18302-18313.
75. Herz HM, Garruss A, Shilatifard A,. SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem Sci 2013; 38: 621-639.
76. Kassis JA, Brown JL,. Polycomb group response elements in Drosophila and vertebrates. Adv Genet 2013; 81: 83-118.
77. Mendenhall EM, Koche RP, Truong T, et al., GC-rich sequence elements recruit PRC2 in mammalian ES cells. PLoS Genet 2010; 6: e1001244.
78. Lynch MD, Smith AJ, De Gobbi M, et al., An interspecies analysis reveals a key role for unmethylated CpG dinucleotides in vertebrate Polycomb complex recruitment. EMBO J 2012; 31: 317-329.
79. Yap DB, Chu J, Berg T, et al., Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood 2011; 117: 2451-2459.
80. Nikoloski G, Langemeijer SM, Kuiper RP, et al., Somatic mutations of the histone methyltransferase gene EZH2 in myelodysplastic syndromes. Nature Genet 2010; 42: 665-667.
81. Morin RD, Johnson NA, Severson TM, et al., Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nature Genet 2010; 42: 181-185.
82. Zhang J, Ding L, Holmfeldt L, et al., The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature 2012; 481: 157-163.
83. Simon C, Chagraoui J, Krosl J, et al., A key role for EZH2 and associated genes in mouse and human adult T-cell acute leukemia. Genes Dev 2012; 26: 651-656.
84. Hock H., A complex Polycomb issue: the two faces of EZH2 in cancer. Genes Dev 2012; 26: 751-755.
85. Lund K, Adams PD, Copland M,. EZH2 in normal and malignant hematopoiesis. Leukemia 2014; 28: 44-49.
86. Varambally S, Cao Q, Mani RS, et al., Genomic loss of microRNA-101 leads to overexpression of histone methyltransferase EZH2 in cancer. Science 2008; 322: 1695-1699.
87. Friedman JM, Liang G, Liu CC, et al., The putative tumor suppressor microRNA-101 modulates the cancer epigenome by repressing the Polycomb group protein EZH2. Cancer Res 2009; 69: 2623-2629.
88. Alajez NM, Shi W, Hui AB, et al., Enhancer of Zeste homolog 2 (EZH2) is overexpressed in recurrent nasopharyngeal carcinoma and is regulated by miR-26a, miR-101, and miR-98. Cell Death Dis 2010; 1: e85.
89. Cao P, Deng Z, Wan M, et al., MicroRNA-101 negatively regulates Ezh2 and its expression is modulated by androgen receptor and HIF-1α/HIF-1β. Mol Cancer 2010; 9: 108.
90. Weng AP, Ferrando AA, Lee W, et al., Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004; 306: 269-271.
91. Agrawal N, Frederick MJ, Pickering CR, et al., Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011; 333: 1154-1157.
92. Stransky N, Egloff AM, Tward AD, et al., The mutational landscape of head and neck squamous cell carcinoma. Science 2011; 333: 1157-1160.
93. Gualberto A, Aldape K, Kozakiewicz K, et al. An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control. Proc Natl Acad Sci U S A 1998; 95: 5166-5171.
94. Brosh R, Rotter V,. When mutants gain new powers: news from the mutant p53 field. Nature Rev Cancer 2009; 9: 701-713.
95. Nambiar M, Raghavan SC,. How does DNA break during chromosomal translocations? Nucleic Acids Res 2011; 39: 5813-5825.
96. Krivtsov AV, Armstrong SA,. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev Cancer 2007; 7: 823-833.
97. Daser A, Rabbitts TH,. Extending the repertoire of the mixed-lineage leukemia gene MLL in leukemogenesis. Genes Dev 2004; 18: 965-974.
98. Okada Y, Feng Q, Lin Y, et al., hDOT1L links histone methylation to leukemogenesis. Cell 2005; 121: 167-178.
99. Mueller D, Bach C, Zeisig D, et al., A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 2007; 110: 4445-4454.
100. Krivtsov AV, Feng Z, Lemieux ME, et al., H3K79 methylation profiles define murine and human MLL-AF4 leukemias. Cancer Cell 2008; 14: 355-368.
101. Bernt KM, Zhu N, Sinha AU, et al., MLL-rearranged leukemia is dependent on aberrant H3K79 methylation by DOT1L. Cancer Cell 2011; 20: 66-78.
102. Klose RJ, Kallin EM, Zhang Y., JmjC-domain-containing proteins and histone demethylation. Nature Rev Genet 2006; 7: 715-727.
103. Tsukada Y, Fang J, Erdjument-Bromage H, et al., Histone demethylation by a family of JmjC domain-containing proteins. Nature 2006; 439: 811-816.
104. Ntziachristos P, Tsirigos A, Welstead GG, et al., Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia. Nature 2014; 514: 513-517.
105. Miller SA, Mohn SE, Weinmann AS,. Jmjd3 and UTX play a demethylase-independent role in chromatin remodeling to regulate T-box family member-dependent gene expression. Mol Cell 2010; 40: 594-605.
106. Chen S, Ma J, Wu F, et al., The histone H3 Lys 27 demethylase JMJD3 regulates gene expression by impacting transcriptional elongation. Genes Dev 2012; 26: 1364-1375.
107. Jankowska AM, Makishima H, Tiu RV, et al., Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. Blood 2011; 118: 3932-3941.
108. Kruidenier L, Chung CW, Cheng Z, et al., A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response. Nature 2012; 488: 404-408.
109. Hamamoto R, Saloura V, Nakamura Y,. Critical roles of non-histone protein lysine methylation in human tumorigenesis. Nature Rev Cancer 2015; 15: 110-124.
110. Talbert PB, Henikoff S,. Histone variants-ancient wrap artists of the epigenome. Nature Rev Mol Cell Biol 2010; 11: 264-275.
111. Jang CW, Shibata Y, Starmer J, et al., Histone H3.3 maintains genome integrity during mammalian development. Genes Dev 2015; 29: 1377-1392.
112. Wu G, Broniscer A, McEachron TA, et al., Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nature Genet 2012; 44: 251-253.
113. Schwartzentruber J, Korshunov A, Liu XY, et al., Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482: 226-231.
114. Chan KM, Fang D, Gan H, et al., The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 2013; 27: 985-990.
115. Bender S, Tang Y, Lindroth AM, et al., Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013; 24: 660-672.
116. Lewis PW, Muller MM, Koletsky MS, et al., Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma. Science 2013; 340: 857-861.
117. Venneti S, Garimella MT, Sullivan LM, et al., Evaluation of histone 3 lysine 27 trimethylation (H3K27me3) and enhancer of Zest 2 (EZH2) in pediatric glial and glioneuronal tumors shows decreased H3K27me3 in H3F3A K27M mutant glioblastomas. Brain Pathol 2013; 23: 558-564.
118. Vogelstein B, Papadopoulos N, Velculescu VE, et al., Cancer genome landscapes. Science 2013; 339: 1546-1558.
119. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al., Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009; 10: 223-232.
120. Van der Meulen J, Sanghvi V, Mavrakis K, et al., The H3K27me3 demethylase UTX is a gender-specific tumor suppressor in T-cell acute lymphoblastic leukemia. Blood 2015; 125: 13-21.
121. Tan J, Yang X, Zhuang L, et al., Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cells. Genes Dev 2007; 21: 1050-1063.
122. Qi W, Chan H, Teng L, et al., Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A 2012; 109: 21360-21365.
123. McCabe MT, Ott HM, Ganji G, et al., EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations. Nature 2012; 492: 108-112.
124. Kim W, Bird GH, Neff T, et al., Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nature Chem Biol 2013; 9: 643-650.
125. Verma SK, Tian X, LaFrance LV, et al., Identification of potent, selective, cell-active inhibitors of the histone lysine methyltransferase EZH2. ACS Med Chem Lett 2012; 3: 1091-1096.
126. Knutson SK, Wigle TJ, Warholic NM, et al., A selective inhibitor of EZH2 blocks H3K27 methylation and kills mutant lymphoma cells. Nature Chem Biol 2012; 8: 890-896.
127. Bradley WD, Arora S, Busby J, et al., EZH2 inhibitor efficacy in non-Hodgkin's lymphoma does not require suppression of H3K27 monomethylation. Chem Biol 2014; 21: 1463-1475.
128. Konze KD, Ma A, Li F, et al., An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem Biol 2013; 8: 1324-1334.
129. Xu B, On DM, Ma A, et al., Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia. Blood 2015; 125: 346-357.
130. Garapaty-Rao S, Nasveschuk C, Gagnon A, et al., Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chem Biol 2013; 20: 1329-1339.
131. Greenblatt SM, Nimer SD,. Chromatin modifiers and the promise of epigenetic therapy in acute leukemia. Leukemia 2014; 28: 1396-1406.
132. Easwaran H, Tsai HC, Baylin SB,. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell 2014; 54: 716-727.
133. Lyko F, Foret S, Kucharski R, et al. The honey bee epigenomes: differential methylation of brain DNA in queens and workers. PLoS Biol 2010; 8: e1000506.
134. Lev Maor G, Yearim A, Ast G,. The alternative role of DNA methylation in splicing regulation. Trends Genet 2015; 31: 274-280.
135. Kang HL, Benzer S, Min KT,. Life extension in Drosophila by feeding a drug. Proc Natl Acad Sci U S A 2002; 99: 838-843.
136. Chittka A, Chittka L,. Epigenetics of royalty. PLoS Biol 2010; 8: e1000532.
137. Spannhoff A, Kim YK, Raynal NJ, et al., Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep 2011; 12: 238-243.
138. Li X, Huang C, Xue Y,. Contribution of lipids in honeybee (Apis mellifera) royal jelly to health. J Med Food 2013; 16: 96-102.
139. Castillo-Fernandez JE, Spector TD, Bell JT,. Epigenetics of discordant monozygotic twins: implications for disease. Genome Med 2014; 6: 60.
140. Fraga MF, Ballestar E, Paz MF, et al., Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 2005; 102: 10604-10609.
141. Lichtenstein P, Holm NV, Verkasalo PK, et al., Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med 2000; 343: 78-85.
142. Roberts NJ, Vogelstein JT, Parmigiani G, et al., The predictive capacity of personal genome sequencing. Sci Transl Med 2012; 4:133ra158.
143. Rodriguez-Cortez VC, Del Pino-Molina L, Rodriguez-Ubreva J, et al., Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naive-to-memory B-cell transition. Nature Commun 2015; 6: 7335.
144. Schmitz RJ, Schultz MD, Lewsey MG, et al., Transgenerational epigenetic instability is a source of novel methylation variants. Science 2011; 334: 369-373.
145. Greer EL, Maures TJ, Ucar D, et al., Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 2011; 479: 365-371.
146. Ng SF, Lin RC, Laybutt DR, et al., Chronic high-fat diet in fathers programs beta-cell dysfunction in female rat offspring. Nature 2010; 467: 963-966.
147. Dias BG, Ressler KJ,. Parental olfactory experience influences behavior and neural structure in subsequent generations. Nature Neurosci 2014; 17: 89-96.
148. Heard E, Martienssen RA,. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 2014; 157: 95-109.
149. Rando OJ, Simmons RA,. I'm eating for two: parental dietary effects on offspring metabolism. Cell 2015; 161: 93-105.
150. Holland ML, Rakyan VK,. Transgenerational inheritance of non-genetically determined phenotypes. Biochem Soc Trans 2013; 41: 769-776.
151. Dunham I, Kundaje A, Aldred SF, et al., An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489: 57-74.
152. Andersson R, Gebhard C, Miguel-Escalada I, et al., An atlas of active enhancers across human cell types and tissues. Nature 2014; 507: 455-461.
153. Smemo S, Tena JJ, Kim KH, et al., Obesity-associated variants within FTO form long-range functional connections with IRX3. Nature 2014; 507: 371-375.
154. Sur IK, Hallikas O, Vaharautio A, et al., Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors. Science 2012; 338: 1360-1363.
155. Kim H, Kim JS,. A guide to genome engineering with programmable nucleases. Nature Rev Genet 2014; 15: 321-334.
156. Mendenhall EM, Williamson KE, Reyon D, et al., Locus-specific editing of histone modifications at endogenous enhancers. Nature Biotechnol 2013; 31: 1133-1136.
157. Hilton IB, D'Ippolito AM, Vockley CM, et al., Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nature Biotechnol 2015; 33: 510-517.
158. Tebas P, Stein D, Tang WW, et al., Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med 2014; 370: 901-910.
159. Genovese P, Schiroli G, Escobar G, et al., Targeted genome editing in human repopulating haematopoietic stem cells. Nature 2014; 510: 235-240.
160. Cox DB, Platt RJ, Zhang F,. Therapeutic genome editing: prospects and challenges. Nature Med 2015; 21: 121-131.
161. Lanphier E, Urnov F, Haecker SE, et al., Don't edit the human germ line. Nature 2015; 519: 410-411.
162. Higgs DR, Goodbourn SE, Lamb J, et al., Alpha-thalassaemia caused by a polyadenylation signal mutation. Nature 1983; 306: 398-400.
163. Bhatia S, Bengani H, Fish M, et al., Disruption of autoregulatory feedback by a mutation in a remote, ultraconserved PAX6 enhancer causes aniridia. Am J Hum Genet 2013; 93: 1126-1134.
164. Aran D, Sabato S, Hellman A,. DNA methylation of distal regulatory sites characterizes dysregulation of cancer genes. Genome Biol 2013; 14: R21.
165. Higgs DR,. The molecular basis of alpha-thalassemia. Cold Spring Harb Perspect Med 2013; 3: a011718.
166. Kioussis D, Vanin E, deLange T, et al., Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia. Nature 1983; 306: 662-666.
167. Tufarelli C, Stanley JA, Garrick D, et al., Transcription of antisense RNA leading to gene silencing and methylation as a novel cause of human genetic disease. Nature Genet 2003; 34: 157-165.
168. Fearnhead NS, Britton MP, Bodmer WF,. The ABC of APC. Hum Mol Genet 2001; 10: 721-733.
169. Balasubramani A, Larjo A, Bassein JA, et al., Cancer-associated ASXL1 mutations may act as gain-of-function mutations of the ASXL1-BAP1 complex. Nature Commun 2015; 6: 7307.
170. Noubissi FK, Elcheva I, Bhatia N, et al., CRD-BP mediates stabilization of βTrCP1 and c-myc mRNA in response to β-catenin signalling. Nature 2006; 441: 898-901.
171. Gustafson WC, Weiss WA,. Myc proteins as therapeutic targets. Oncogene 2010; 29: 1249-1259.
172. Bosher JM, Totty NF, Hsuan JJ, et al., A family of AP-2 proteins regulates c-erbB-2 expression in mammary carcinoma. Oncogene 1996; 13: 1701-1707.
173. Nagarajan RP, Zhang B, Bell RJ, et al., Recurrent epimutations activate gene body promoters in primary glioblastoma. Genome Res 2014; 24: 761-774.
174. King CR, Kraus MH, Aaronson SA,. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science 1985; 229: 974-976.
175. Giorgio E, Robyr D, Spielmann M, et al., A large genomic deletion leads to enhancer adoption by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD). Hum Mol Genet 2015; 24: 3143-3154.
176. Adams JM, Harris AW, Pinkert CA, et al., The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985; 318: 533-538.
177. Huether R, Dong L, Chen X, et al., The landscape of somatic mutations in epigenetic regulators across 1000 paediatric cancer genomes. Nature Commun 2014; 5: 3630.
178. Mar BG, Bullinger L, Basu E, et al., Sequencing histone-modifying enzymes identifies UTX mutations in acute lymphoblastic leukemia. Leukemia 2012; 26: 1881-1883.
179. Kar SA, Jankowska A, Makishima H, et al., Spliceosomal gene mutations are frequent events in the diverse mutational spectrum of chronic myelomonocytic leukemia but largely absent in juvenile myelomonocytic leukemia. Haematologica 2012; 98: 107-113.
180. Gelsi-Boyer V, Trouplin V, Adelaide J, et al., Mutations of polycomb-associated gene ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J Haematol 2009; 145: 788-800.