Изучение тканеспецифического метилирования протяженных геномных локусов тема диссертации и автореферата по ВАК РФ 03.00.03, кандидат биологических наук Скворцова, Юлия Валентиновна

• Скворцова, Юлия Валентиновна
• кандидат биологических наук
• 2007

Оглавление диссертации кандидат биологических наук Скворцова, Юлия Валентиновна

Список сокращений

1. Введение

2. Литобзор «Метилирование ДНК у млекопитающих.»

2,1. Введение

2.2 Распределение метилированных цитозинов в геноме млекопитающих.

2.3. Клеточный аппарат метилирования ДНК и ремоделирования хроматина.

2.4. Изменения паттерна метилирования ДНК в онтогенезе.

2.5. Метилирование и импринтинг.

2.6. Нарушения метилирование ДНК при развитии заболеваний.

2.7. Влияние окружающей среды на метилирование ДНК.

Введение диссертации (часть автореферата) на тему «Изучение тканеспецифического метилирования протяженных геномных локусов»

Для ДНК человека и млекопитающих известна одна эпигенетическая мутация метилирование цитозина по пятому положению в составе динуклеотида CpG. Важность ее для развития организма подтверждается несколько десятков лет, но к настоящему моменту окончательно не выяснены механизмы ее функционирования. На сегоднящний день подтверждено, что распределение метилированных цитозинов в геномной ДНК, так называемый патгерн метилирования, наследуется в ряду клеточных поколений и имеет видовую и тканевую специфичность. Также известно, что метилирование ДНК задействовано в аллельно-специфическом импринтинге, сопровождает инактивацию интегрированных экзогенных последовательностей и инактивацию генов онкосупрессоров при канцерогенезе. Известны белки, отвечающие за приобретение паттерна метилирования в эмбриогенезе и поддерживающие его в дальнейшем онтогенезе. Для ряда случаев доказана взаимосвязь между метилированием ДНК и другими эпигенетическими факторами, но неизвестно какая из этих модификаций является определяющей в реорганизации структуры хроматина. Показано, что для некоторых и генов существует ДНК корреляция между их регуляторных транскрипционной активностью метилированием последовательностей. Также известны метил-связывающие белки, которые взаимодействуют с факторами и трансфакторами транскрипции. Однако на данный момент утверждение о роли влияния метилирования ДНК на транскрипцию генов остается не до конца аргументированным. Для изучения функционального значения метилирования, в частности, механизмов влияния метилирования на экспрессию генов, необходим комплексный подход, в котором рассматривается не один конкретный ген, а протяженный полигенный район, содержащий гены, псевдогены, различные повторы, локус-контролирующие районы, инсуляторы и другие регуляторные элементы. Поэтому чрезвычайно важным является получение данных, детально описывающих метилирование протяженных областей. Анализ корреляции множества факторов, проведенный на таком полигенном уровне в разных тканях, в том числе опухолевых, может позволить делать статистически достоверные выводы о функциях метилирования в регуляции транскрипции в протяженных районах ДНК. Разработке такого подхода посвящена данная работа.Цели и задачи работы. Целью данной работы являлось создание нового экспериментального подхода для изучения тканеспецифического метилирования протяженных геномных участков (млн. и.о.) Бьии поставлены следующие задачи: 1. Разработать метод, позволяющий изучать распределение метилирования в протяженных участках ДНК, 2. Используя разработанный метод, провести сравнительный анализ метилирования участка 19-ой хромосомы в ДНК нормальных и опухолевых тканях, а также клеточной линни. 3. Провести функциональный анализ найденных дифференциально метилированных локусов, для чего сравнить состояние хроматина и уровень экспрессии генов, находящихся в этих локусах.ЛИТОБЗОР. МЕТИЛИРОВАНИЕ ДНК У МЛЕКОПИТАЮЩИХ. 2,1. Введение.Термин «эпигенетика» ввел в 1940 г, английский эмбриолог и генетик Конрад Вадцингтон. Под ним он определял процесс влияния окружающей среды на гены, за счет которого формируется фенотип [Waddington, 1942]. Сейчас под ним понимают клеточные механизмы регуляции и изменения экспрессии генов [Jaenisch et al., 2003]. Эпигенетические механизмы могут действовать на трех уровнях клеточной организации: структура хроматина и регуляция транскрипции; регуляция трансляции; регуляции топографического распределения белков и их функций в различных процессах клетки [Korochkin, 2006]. Впервые в группе Ванюшина Б.Ф. была показана видовая, тканевая, органоидная и возрастная специфичность распределения в геномной ДНК метилированных по пятому положению цитозинов [Vanyushin et al., 1962], [Romanov et al, 1981], [Kimos et al., 1981]. Далее было показано, что метилирование цитозина по пятому положению в составе динуклеотида CpG является единственной эпигенетической модификацией человека и млекопитающих [Vanyushin et al., 1973]. В 1975 г. на основе тех фактов, что метилирование цитозина по пятому положению в составе динуклеотида CpG является единственной эпигенетической модификацией человека и млекопитающих, а также специфичности паттернов метилирования бьша вьщвинута модель, предполагающая, что метилирование ДНК является одним из факторов, влияющих на экспрессию генов [Riggs, 1975]. 2,2. Распределение метилированных цитозинов в геноме млекопитающих. Метилированный цитозин у млекопитающих находится в составе CpG динуклеотида, который высоко представлен в их геноме. Так, у человека частота его встречаемости составляет 23%, а у мьши 19%. На основе данных биоинформатической обработки последовательностей ДНК генома было выявлено, что у человека 51% CpG содержится в повторяющихся и 49% CpG в уникальных последовательностях, а у мыши: 35% в повторяющихся и 64% в уникальных [Yoder et al., 1997]. Исследования с использованием метилчувствительной рестриктазы Hpall показали, что в геноме млекопитающих в среднем примерно 55-70% CpG метилировано [Bird, 1980]. Сравнительный анализ последовательностей фрагментов, полученных после рестрикции Hpall показал, что в геноме неметилированные CCGG сайты расположены в основном в C+G богатых областях, соответственно и CpG в них чаще встречается, чем в других районах. Эти районы стали называть «CpG-островки» [Bird, 1986]. Критерии для их определения были даны на основе особенностей известных на тот момент последовательностей с часто встречающимися сайтами рестрикции Hpall (Hpall tiny fragments, HTFs) и данными из баз геномных последовательностей на 1985 г. По этому определению, которым пользуются до сих пор, CpG-островок это последовательность ДНК длиной 200 п.о. и более, в которой содержание C+G составляет более 50%, а частота встречаемости CpG выше 0,6 [Gardiner-Garden et al, 1987], У человека примерно половина генов экспрессируется в большинстве тканей и содержит CpG-островки, которые в основном не метилированы и находятся в промоторах этих генов [Ioshikhes et al., 2000], [Ponger et al., 2001]. Однако некоторые неметилированные CpG-островки ассоциированы с тканеспецифическими генами, которые активируются в определенных типах тканей при их дифференцировке [Bird, 2002]. Другая группа CpG-островков, которые метилированы, находится в промоторах импринтируемых генов и генов инактивированной Х-хромосомы [Bird, 2002]. Использование данного выше определения CpG-островков дает возможность найти их также и в промоторах некоторых эндогенных ретроэлементов. Биоинформатический анализ 21 и 22 хромосом позволил выявить отличие между CpGостровками уникальных последовательностей и CpG-островками повторяющихся элементов. Оказалось, что CpG-островки уникальных последовательностей промоторов генов, как правило, имеют длину более 500 п.о. и содержание C+G в них более 55% [Takai et al., 2002]. Многочисленные исследования подтверждают гетерогенность геномов растений и животных по содержанию нуклеотидов и существование протяженных C+G богатых областей, длина которых достигает несколько сотен тысяч п.о. [Salinas et al, 1988], [Bemardi et al, 1988]. Интересно, что с гетерогенностью нуклеотидного состава взаимосвязана гетерогеннность различных функциональных особенностей генома. Замечено, что повьппенное C+G содержание положительно коррелирует с высоким содержанием CpG-островков [Jabbari et al, 1998] и генов [Federico et al, 2000], маленьким размером интронов [Lander et al, 2001], высокой транскрипционной активностью [Arhondakis et al., 2004], высокой представленностью AluSINEs [Lander et al., 2001], низкой представленностью LI LINE [Pavlicek et al., 2001], ранним временем репликации [Smith et al., 1999] и высокой частотой рекомбинации при мейозе [Kong et al., 2002]. В связи с этим интересен факт, что импринтируемые гены (гены, специфически экспрессирующиеся с одного из родительских аллелей), имеющие специфическую экспрессию материнского аллеля, находятся в C+G богатых областях, а имеющие специфическую экспрессию отцовского аллеля в районах с высоким содержанием

Заключение диссертации по теме «Молекулярная биология», Скворцова, Юлия Валентиновна

выводы.

1. Разработан новый метод анализа распределения тканеспецифического метилирования на протяженных участках геномной ДНК.

2. Впервые проведен подробный анализ распределения метилирования в локусе FXYD5 -СОХ7А1 19 хромосомы человека длиной 1,02 млн. п.о. для различных образцов геномной ДНК (паренхимы и семиномы яичка, нормальной и опухолевой тканей легкого, клеточной линии А549 аденокарциномы легкого). Показано, что различия между паттернами метилирования локуса FXYD5 - СОХ7А1 в исследованных нормальных и опухолевых тканях минимальны.

3. Изучена транскрипционная активность генов СОХ7А1, СКАР1, CAPNS1, находящихся в области, гипометилированной в нормальных тканях по сравнению с опухолевыми. Показано, что уровень экспрессии этих генов выше в нормальных тканях, что коррелирует с гипометилированным состоянием их промоторных областей.

4. Показано, что для клеточной линии А549 характерно гиперметилирование протяженной ген-содержащей области длиной 30 тыс. п.о., не обнаруженное в других исследованных тканях.

5. Сравнительный анализ транскрипционной активности генов MAG и НАМР в разных тканях продемонстрировал ее независимость от метилирования ДНК, что доказывает отсутствие обязательной зависимости между метилированием локусов этих генов и уровнем их транскрипции.

Список литературы диссертационного исследования кандидат биологических наук Скворцова, Юлия Валентиновна, 2007 год

1. Aapola U, Liiv I and Peterson P, Imprinting regulator DNMT3L is a transcriptional repressor associated with histone deacetylase activity (2002) Nucleic Acids Res, 30, 3602-8

2. Adenot PG, Mercier Y, Renard JP and Thompson EM, Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos (1997) Development, 124,4615-25

3. Agarwal N, Hardt T, Brero A, Nowak D, Rothbauer U, Becker A, Leonhardt H and Cardoso MC, MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation (2007) Nucleic Acids Res, 35,5402-8

4. Allen E, Horvath S, Tong F, Kraft P, Spiteri E, Riggs AD and Marahrens Y, High concentrations of long interspersed nuclear element sequence distinguish monoallelically expressed genes (2003) Proc Natl Acad Sci USA, 100, 9940-5

5. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U and Zoghbi HY, Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2 (1999) Nat Genet, 23,185-8

6. Antequera F, Structure, function and evolution of CpG island promoters (2003) Cell Mol Life Sci, 60,1647-58

7. Anway MD, Cupp AS, Uzumcu M and Skinner MK, Epigenetic transgenerational actions of endocrine disruptors and male fertility (2005) Science, 308,1466-9

8. Aoki F, Worrad DM and Schultz RM, Regulation of transcriptional activity during the first and second cell cycles in the preimplantation mouse embryo (1997) Dev Biol, 181, 296-307

9. Araujo FD, Croteau S, Slack AD, Milutinovic S, Bigey P, Price GB, Zannis-Hadjopoulos M and Szyf M, The DNMT1 target recognition domain resides in the N terminus (2001) J Biol Chem, 276,6930-6

10. Arhondakis S, Auletta F, Torelli G and D'Onofrio G, Base composition and expression level of human genes (2004) Gene, 325,165-9

11. Attema JL, Papathanasiou P, Forsberg EC, Xu J, Smale ST and Weissman IL, Epigenetic characterization of hematopoietic stem cell differentiation using miniChIP and bisulfite sequencing analysis (2007) Proc Natl Acad Sci USA, 104,12371-6

12. Bachman KE, Rountree MR and Baylin SB, Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin (2001) J Biol Chem, 276,32282-7

13. Bachman KE, Park BH, Rhee I, Rajagopalan H, Herman JG, Baylin SB, Kinzler KW and Vogelstein B, Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene (2003) Cancer Cell, 3, 89-95

14. Bader S, Walker M, Hendrich B, Bird A, Bird C, Hooper M and Wyllie A, Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency (1999) Oncogene, 18,8044-7

15. Ballas N, Grunseich C, Lu DD, Speh JC and Mandel G, REST and its corepressors mediate plasticity of neuronal gene chromatin throughout neurogenesis (2005) Cell, 121, 645-57

16. Ballestar E, Paz MF, Valle L, Wei S, Fraga MF, Espada J, Cigudosa JC, Huang TH and Esteller M, Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer (2003) Embo J, 22, 6335-45

17. Balmer D, Arredondo J, Samaco RC and LaSalle JM, MECP2 mutations in Rett syndrome adversely affect lymphocyte growth, but do not affect imprinted gene expression in blood or brain (2002) Hum Genet, 110,545-52

18. Baylin SB and Ohm JE, Epigenetic gene silencing in cancer a mechanism for early oncogenic pathway addiction? (2006) Nat Rev Cancer, 6,107-16

19. Bell AC and Felsenfeld G, Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene (2000) Nature, 405,482-5

20. Berger SL, The complex language of chromatin regulation during transcription (2007) Nature, 447,407-12

21. Bernardi G, Mouchiroud D and Gautier C, Compositional patterns in vertebrate genomes: conservation and change in evolution (1988) J Mol Evol, 28,7-18

22. Bestor TH, The DNA methyltransferases of mammals (2000) Hum Mol Genet, 9, 2395402

23. Bienvenu T and Chelly J, Molecular genetics of Rett syndrome: when DNA methylation goes unrecognized (2006) Nat Rev Genet, 7,415-26

24. Bird AP, DNA methylation and the frequency of CpG in animal DNA (1980) Nucleic Acids Res, 8,1499-504

25. Bird AP, CpG-rich islands and the function of DNA methylation (1986) Nature, 321,209.13

26. Bird AP and Wolffe AP, Methylation-induced repression-belts, braces, and chromatin (1999) Cell, 99,451-4

27. Bird A, DNA methylation patterns and epigenetic memory (2002) Genes Dev, 16, 6-21

28. Blanco-Betancourt CE, Moncla A, Milili M, Jiang YL, Viegas-Pequignot EM, Roquelaure B, Thuret I and Schiff C, Defective B-cell-negative selection and terminal differentiation in the ICF syndrome (2004) Blood, 103,2683-90

29. Blewitt ME, Vickaryous NK, Paldi A, Koseki H and Whitelaw E, Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice (2006) PLoS Genet, 2, e49

30. Braun RE, Packaging paternal chromosomes with protamine (2001) Nat Genet, 28,10-2

31. Brero A, Easwaran HP, Nowak D, Grunewald I, Cremer T, Leonhardt H and Cardoso MC, Methyl CpG-binding proteins induce large-scale chromatin reorganization during terminal differentiation (2005) J Cell Biol, 169, 733-43

32. Brueckner B, Stresemann C, Kuner R, Mund C, Musch T, Meister M, Sultmann H and Lyko F, The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function (2007) Cancer Res, 67,1419-23

33. Burgers WA, Fuks F and Kouzarides T, DNA methyltransferases get connected to chromatin (2002) Trends Genet, 18,275-7

34. Carlson LL, Page AW and Bestor TH, Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting (1992) Genes Dev, 6,2536-41

35. Chandler SP, Guschin D, Landsberger N and Wolffe AP, The methyl-CpG binding transcriptional repressor MeCP2 stably associates with nucleosomal DNA (1999) Biochemistry,38, 7008-18

36. Chen RZ, Pettersson U, Beard C, Jackson-Grusby L and Jaenisch R, DNA hypomethylation leads to elevated mutation rates (1998) Nature, 395,89-93

37. Chen RZ, Akbarian S, Tudor M and Jaenisch R, Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice (2001) Nat Genet, 27,327-31

38. Chen WG, Chang Q, Lin Y, Meissner A, West AE, Griffith EC, Jaenisch R and Greenberg ME, Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2 (2003) Science, 302, 885-9

39. Chen WY, Zeng X, Carter MG, Morrell CN, Chiu Yen RW, Esteller M, Watkins DN, Herman JG, Mankowski JL and Baylin SB, Heterozygous disruption of Hicl predisposes mice to a gender-dependent spectrum of malignant tumors (2003) Nat Genet, 33,197-202

40. Choi IS, Estecio MR, Nagano Y, Kim do H, White JA, Yao JC, Issa JP and Rashid A, Hypomethylation of LINE-1 and Alu in well-differentiated neuroendocrine tumors (pancreatic endocrine tumors and carcinoid tumors) (2007) Mod Pathol, 20,802-10

41. Clark SJ, Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis (2007) Hum Mol Genet, 16 Spec No 1, R88-95

42. Cross SH, Charlton JA, Nan X and Bird AP, Purification of CpG islands using a methylated DNA binding column (1994) Nat Genet, 6,236-44

43. Cross SH, Meehan RR, Nan X and Bird A, A component of the transcriptional repressor MeCPl shares a motif with DNA methyltransferase and HRX proteins (1997) Nat Genet, 16, 256-9

44. Cross SH, Clark VH and Bird AP, Isolation of CpG islands from large genomic clones (1999) Nucleic Acids Res, 27, 2099-107

45. Cui H, Cruz-Correa M, Giardiello FM, Hutcheon DF, Kafonek DR, Brandenburg S, Wu Y, He X, Powe NR and Feinberg AP, Loss of IGF2 imprinting: a potential marker of colorectal cancer risk (2003) Science, 299,1753-5

46. Daniel JM, Spring CM, Crawford HC, Reynolds AB and Baig A, The pl20(ctn)-binding partner Kaiso is a bi-modal DNA-binding protein that recognizes both a sequence-specific consensus and methylated CpG dinucleotides (2002) Nucleic Acids Res, 30,2911-9

47. De Smet C, Lurquin C, Lethe B, Martelange V and Boon T, DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter (1999) Mol Cell Biol, 19,7327-35

48. DeBaun MR and Tucker MA, Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry (1998) J Pediatr, 132,398-400

49. DeBaun MR, Niemitz EL, McNeil DE, Brandenburg SA, Lee MP and Feinberg AP, Epigenetic alterations of H19 and LIT1 distinguish patients with Beckwith-Wiedemann syndrome with cancer and birth defects (2002) Am J Hum Genet, 70,604-11

50. Deplus R, Brenner C, Burgers WA, Putmans P, Kouzarides T, de Launoit Y and Fuks F, Dnmt3L is a transcriptional repressor that recruits histone deacetylase (2002) Nucleic Acids Res, 30,3831-8

51. Devon RS and Brookes AJ, Coincidence cloning. Taking the coincidences out of genome analysis (1996) Mol Biotechnol, 5,243-52

52. Diaz-Meyer N, Yang Y, Sait SN, Maher ER and Higgins MJ, Alternative mechanisms associated with silencing of CDKN1C in Beckwith-Wiedemann syndrome (2005) J Med Genet, 42, 648-55

53. Doherty AS, Bartolomei MS and Schultz RM, Regulation of stage-specific nuclear translocation of Dnmtlo during preimplantation mouse development (2002) Dev Biol, 242, 25566

54. Dong A, Yoder JA, Zhang X, Zhou L, Bestor TH and Cheng X, Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA (2001) Nucleic Acids Res, 29,439-48

55. Eads CA, Danenberg KD, Kawakami K, Saltz LB, Blake C, Shibata D, Danenberg PV and Laird PW, MethyLight: a high-throughput assay to measure DNA methylation (2000) Nucleic Acids Res, 28, E32

56. Easwaran HP, Schermelleh L, Leonhardt H and Cardoso MC, Replication-independent chromatin loading of Dnmtl during G2 and M phases (2004) EMBO Rep, 5,1181-6

57. Eden A, Gaudet F, Waghmare A and Jaenisch R, Chromosomal instability and tumors promoted by DNA hypomethylation (2003) Science, 300,455

58. Ehrlich M, Hopkins NE, Jiang G, Dome JS, Yu MC, Woods CB, Tomlinson GE, Chintagumpala M, Champagne M, Dillerg L, Parham DM and Sawyer J, Satellite DNA hypomethylation in karyotyped Wilms tumors (2003) Cancer Genet Cytogenet, 141,97-105

59. Esteller M, Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes (2000) Eur J Cancer, 36,2294-300

60. Esteller M, Corn PG, Baylin SB and Herman JG, A gene hypermethylation profile of human cancer (2001) Cancer Res, 61, 3225-9

61. Esteve PO, Chin HG, Smallwood A, Feehery GR, Gangisetty O, Karpf AR, Carey MF and Pradhan S, Direct interaction between DNMT1 and G9a coordinates DNA and histone methylation during replication (2006) Genes Dev, 20,3089-103

62. Fatemi M, Hermann A, Gowher H and Jeltsch A, Dnmt3a and Dnmtl functionally cooperate during de novo methylation of DNA (2002) Eur J Biochem, 269,4981-4

63. Federico C, Andreozzi L, Saccone S and Bernardi G, Gene density in the Giemsa bands of human chromosomes (2000) Chromosome Res, 8, 737-46

64. Feil R, Boyano MD, Allen ND and Kelsey G, Parental chromosome-specific chromatin conformation in the imprinted U2afl-rsl gene in the mouse (1997) J Biol Chem, 272,20893-900

65. Feinberg AP and Vogelstein B, Hypomethylation distinguishes genes of some human cancers from their normal counterparts (1983) Nature, 301, 89-92

66. Feinberg AP and Tycko B, The history of cancer epigenetics (2004) Nat Rev Cancer, 4,143.53

67. Feinberg AP, Phenotypic plasticity and the epigenetics of human disease (2007) Nature, 447,433-40

68. Feng Q and Zhang Y, The MeCPl complex represses transcription through preferential binding, remodeling, and deacetylating methylated nucleosomes (2001) Genes Dev, 15, 827-32

69. Filion GJ, Zhenilo S, Salozhin S, Yamada D, Prokhortchouk E and Defossez PA, A family of human zinc finger proteins that bind methylated DNA and repress transcription (2006) Mol Cell Biol, 26,169-81

70. Fitzpatrick GV, Pugacheva EM, Shin JY, Abdullaev Z, Yang Y, Khatod K, Lobanenkov VV and Higgins MJ, Allele-specific binding of CTCF to the multipartite imprinting control region KvDMRl (2007) Mol Cell Biol, 27,2636-47

71. Florl AR, Lower R, Schmitz-Drager BJ and Schulz WA, DNA methylation and expression of LINE-1 and HERV-K provirus sequences in urothelial and renal cell carcinomas (1999) Br J Cancer, 80,1312-21

72. Florl AR, Steinhoff C, Muller M, Seifert HH, Hader C, Engers R, Ackermann R and Schulz WA, Coordinate hypermethylation at specific genes in prostate carcinoma precedes LINE-1 hypomethylation (2004) Br J Cancer, 91,985-94

73. Foumier C, Goto Y, Ballestar E, Delaval K, Hever AM, Esteller M and Feil R, Allele-specific histone lysine methylation marks regulatory regions at imprinted mouse genes (2002) Embo J, 21,6560-70

74. Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL and Paul CL, A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands (1992) Proc Natl Acad Sci USA, 89,1827-31

75. Fujita N, Takebayashi S, Okumura K, Kudo S, Chiba T, Saya H and Nakao M, Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms (1999) Mol Cell Biol, 19,6415-26

76. Fujita N, Shimotake N, Ohki I, Chiba T, Saya H, Shirakawa M and Nakao M, Mechanism of transcriptional regulation by methyl-CpG binding protein MBD1 (2000) Mol Cell Biol, 20,5107-18

77. Fuks F, Burgers WA, Godin N, Kasai M and Kouzarides T, Dnmt3a binds deacetylases and is recruited by a sequence-specific repressor to silence transcription (2001) Embo J, 20, 2536-44

78. Fuks F, Hurd PJ, Wolf D, Nan X, Bird AP and Kouzarides T, The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation (2003) J Biol Chem, 278,4035-40

79. Fuks F, DNA methylation and histone modifications: teaming up to silence genes (2005) Curr Opin Genet Dev, 15,490-5

80. Futscher BW, Oshiro MM, Wozniak RJ, Holtan N, Hanigan CL, Duan H and Domann FE, Role for DNA methylation in the control of cell type specific maspin expression (2002) Nat Genet, 31,175-9.

81. Gardiner-Garden M and Frommer M, CpG islands in vertebrate genomes (1987) J Mol Biol, 196,261-82

82. Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW, Leonhardt H and Jaenisch R, Induction of tumors in mice by genomic hypomethylation (2003) Science, 300, 489-92

83. Georgel PT, Horowitz-Scherer RA, Adkins N, Woodcock CL, Wade PA and Hansen JC, Chromatin compaction by human MeCP2. Assembly of novel secondary chromatin structures in the absence of DNA methylation (2003) J Biol Chem, 278,32181-8

84. Gilbert N, Boyle S, Fiegler H, Woodfine K, Carter NP and Bickmore WA, Chromatin architecture of the human genome: gene-rich domains are enriched in open chromatin fibers (2004) Cell, 118, 555-66

85. Gilbert N, Thomson I, Boyle S, Allan J, Ramsahoye В and Bickmore WA, DNA methylation affects nuclear organization, histone modifications, and linker histone binding but not chromatin compaction (2007) J Cell Biol, 177,401-11

86. Giovannucci E, Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies (2004) J Nutr, 134,2475S-2481S

87. Glenn CC, Saitoh S, Jong MT, Filbrandt MM, Surti U, Driscoll DJ and Nicholls RD, Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene (1996) Am J Hum Genet, 58, 335-46

88. Goll MG, Kirpekar F, Maggert KA, Yoder JA, Hsieh CL, Zhang X, Golic KG, Jacobsen SE and Bestor TH, Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2 (2006) Science, 311, 395-8

89. Gotzinger N, Sauter M, Roemer К and Mueller-Lantzsch N, Regulation of human endogenous retrovirus-K Gag expression in teratocarcinoma cell lines and human tumours (1996) J Gen Virol, 77 (Pt 12), 2983-90

90. Gowher H, Liebert K, Hermann A, Xu G and Jeltsch A, Mechanism of stimulation of catalytic activity of Dnmt3A and Dnmt3B DNA-(cytosine-C5)-methyltransferases by Dnmt3L (2005) J Biol Chem, 280,13341-8

91. Greally JM, Short interspersed transposable elements (SINEs) are excluded from imprinted regions in the human genome (2002) Proc Natl Acad Sci USA, 99,327-32

92. Greger V, Passarge E, Hopping W, Messmer E and Horsthemke B, Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma (1989) Hum Genet, 83,155-8

93. Guran S, Bahce M, Beyan C, Korkmaz К and Yalcin A, P53, pl5INK4B, pl6INK4A and p57KIP2 mutations during the progression of chronic myeloid leukemia (1998) Haematologia (Budap), 29,181-93

94. Guy J, Hendrich B, Holmes M, Martin JE and Bird A, A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome (2001) Nat Genet, 27,322-6

95. Haaf T, The battle of the sexes after fertilization: behaviour of paternal and maternal chromosomes in the early mammalian embryo (2001) Chromosome Res, 9,263-71

96. Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J and Surani MA, Epigenetic reprogramming in mouse primordial germ cells (2002) Mech Dev, 117,15-23

97. Hanahan D and Weinberg RA, The hallmarks of cancer (2000) Cell, 100,57-70

98. Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM and Gartler SM, The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome (1999) Proc Natl Acad Sci USA, 96,14412-7

99. Harikrishnan KN, Chow MZ, Baker EK, Pal S, Bassal S, Brasacchio D, Wang L, Craig JM, Jones PL, Sif S and El-Osta A, Brahma links the SWI/SNF chromatin-remodeling complex with MeCP2-dependent transcriptional silencing (2005) Nat Genet, 37,254-64

100. Hark AT, Schoenherr CJ, Katz DJ, Ingram RS, Levorse JM and Tilghman SM, CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus (2000) Nature, 405,486-9

101. Heitmann B, Maurer T, Weitzel JM, Stratling WH, Kalbitzer HR and Brunner E, Solution structure of the matrix attachment region-binding domain of chicken MeCP2 (2003) Eur J Biochem, 270, 3263-70

102. Hendrich В and Bird A, Identification and characterization of a family of mammalian methyl-CpG binding proteins (1998) Mol Cell Biol, 18,6538-47

103. Hendrich B, Abbott C, McQueen H, Chambers D, Cross S and Bird A, Genomic structure and chromosomal mapping of the murine and human Mbdl, Mbd2, Mbd3, and Mbd4 genes (1999) Mamm Genome, 10, 906-12

104. Hendrich B, Hardeland U, Ng HH, Jiricny J and Bird A, The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites (1999) Nature, 401,301-4

105. Hendrich В and Bird A, Mammalian methyltransferases and methyl-CpG-binding domains: proteins involved in DNA methylation (2000) Curr Top Microbiol Immunol, 249, 5574

106. Hendrich B, Guy J, Ramsahoye B, Wilson VA and Bird A, Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development (2001) Genes Dev, 15,710-23

107. Hendrich В and Tweedie S, The methyl-CpG binding domain and the evolving role of DNA methylation in animals (2003) Trends Genet, 19,269-77

108. Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB, Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands (1996) Proc Natl Acad Sci USA, 93, 9821-6

109. Herman JG and Baylin SB, Gene silencing in cancer in association with promoter hypermethylation (2003) N Engl J Med, 349,2042-54

110. Hermann A, Gowher H and Jeltsch A, Biochemistry and biology of mammalian DNA methyltransferases (2004) Cell Mol Life Sci, 61, 2571-87

111. Hermann A, Goyal R and Jeltsch A, The Dnmtl DNA-(cytosine-C5)-methyltransferase methylates DNA processively with high preference for hemimethylated target sites (2004) J Biol Chem, 279,48350-9

112. Hikichi T, Kohda T, Kaneko-Ishino T and Ishino F, Imprinting regulation of the murine Megl/GrblO and human GRB10 genes; roles of brain-specific promoters and mouse-specific CTCF-binding sites (2003) Nucleic Acids Res, 31,1398-406

113. Horike S, Cai S, Miyano M, Cheng JF and Kohwi-Shigematsu T, Loss of silent-chromatin looping and impaired imprinting of DLX5 in Rett syndrome (2005) Nat Genet, 37, 3140

114. Howell CY, Bestor TH, Ding F, Latham KE, Mertineit C, Trasler JM and Chaillet JR, Genomic imprinting disrupted by a maternal effect mutation in the Dnmtl gene (2001) Cell, 104, 829-38

115. Jabbari К and Bernardi G, CpG doublets, CpG islands and Alu repeats in long human DNA sequences from different isochore families (1998) Gene, 224,123-7

116. Jaenisch R and Bird A, Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals (2003) Nat Genet, 33 Suppl, 245-54

117. Jeffery L and Nakielny S, Components of the DNA methylation system of chromatin control are RNA-binding proteins (2004) J Biol Chem, 279,49479-87

118. Jelinic P and Shaw P, Loss of imprinting and cancer (2007) J Pathol, 211,261-8

119. Ji W, Hernandez R, Zhang XY, Qu GZ, Frady A, Varela M and Ehrlich M, DNA demethylation and pericentromeric rearrangements of chromosome 1 (1997) Mutat Res, 379,3341

120. Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J and Wolffe AP, Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription (1998) Nat Genet, 19,187-91

121. Jubb AM, Quirke P and Oates AJ, DNA methylation, a biomarker for colorectal cancer: implications for screening and pathological utility (2003) Ann N Y Acad Sci, 983,251-67

122. Kaneda M, Okano M, Hata K, Sado T, Tsujimoto N, Li E and Sasaki H, Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting (2004) Nature, 429,900-3

123. Kareta MS, Botello ZM, Ennis JJ, Chou С and Chedin F, Reconstitution and mechanism of the stimulation of de novo methylation by human DNMT3L (2006) J Biol Chem, 281, 25893902

124. Karymov MA, Tomschik M, Leuba SH, Caiafa P and Zlatanova J, DNA methylation-dependent chromatin fiber compaction in vivo and in vitro: requirement for linker histone (2001) FasebJ, 15,2631-41

125. Kato Y, Kaneda M, Hata K, Kumaki K, Hisano M, Kohara Y, Okano M, Li E, Nozaki M and Sasaki H, Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse (2007) Hum Mol Genet,

126. Kim SW, Park JI, Spring CM, Sater AK, Ji H, Otchere AA, Daniel JM and McCrea PD, Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and pi 20-catenin (2004) Nat Cell Biol, 6,1212-20

127. Kimura F, Florl AR, Seifert HH, Louhelainen J, Maas S, Knowles MA and Schulz WA, Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder (2001) Br J Cancer, 85,1887-93

128. Kirnos MD, Aleksandrushkina N1 and Vaniushin BF, 5-Methylcytosine in pyrimidine sequences of plant and animal DNA: specificity of methylation. (1981) Biokhimiia, 46,1458-74

129. Kisseljova NP and Kisseljov FL, DNA demethylation and carcinogenesis (2005) Biochemistry (Mosc), 70,743-52

130. Klose RJ, Sarraf SA, Schmiedeberg L, McDermott SM, Stancheva I and Bird AP, DNA binding selectivity of MeCP2 due to a requirement for A/T sequences adjacent to methyl-CpG2005) Mol Cell, 19, 667-78

131. Korochkin LI, What is epigenetics. (2006) Genetika, 42,1156-64

132. Kouidou S, Malousi A, Kyventidis A, Fragou A and Maglaveras N, G:C > A:T mutations and potential epigenetic regulation of p53 in breast cancer (2007) Breast Cancer Res Treat,

133. Kransdorf EP, Wang SZ, Zhu SZ, Langston ТВ, Rupon JW and Ginder GD, MBD2 is a critical component of a methyl cytosine-binding protein complex isolated from primary erythroid cells (2006) Blood, 108,2836-45

134. Krawczak M, Ball EV and Cooper DN, Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes (1998) Am J Hum Genet, 63,474-88

135. Ma Y, Jacobs SB, Jackson-Grusby L, Mastrangelo MA, Torres-Betancourt JA, Jaenisch R and Rasmussen TP, DNA CpG hypomethylation induces heterochromatin reorganization involving the histone variant macroH2A (2005) J Cell Sci, 118,1607-16

136. Maatouk DM, Kellam LD, Mann MR, Lei H, Li E, Bartolomei MS and Resnick JL, DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages (2006) Development, 133,3411-8

137. Magdinier F and WolfFe AP, Selective association of the methyl-CpG binding protein MBD2 with the silent pl4/pl6 locus in human neoplasia (2001) Proc Natl Acad Sci USA, 98, 4990-5

138. Margot JL and Brown ME, A low-density M-type asteroid in the main belt (2003) Science, 300,1939-42

139. Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, Fan G and Sun YE, DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation (2003) Science, 302, 890-3

140. Matsuzaki К, Deng G, Tanaka H, Kakar S, Miura S and Kim YS, The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer (2005) Clin Cancer Res, 11, 8564-9

141. Mayer W, Niveleau A, Walter J, Fundele R and Haaf T, Demethylation of the zygotic paternal genome (2000) Nature, 403,501-2

142. Meehan RR, Lewis JD, McKay S, Kleiner EL and Bird AP, Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs (1989) Cell, 58, 499-507

143. Mertineit C, Yoder JA, Taketo T, Laird DW, Trasler JM and Bestor TH, Sex-specific exons control DNA methyltransferase in mammalian germ cells (1998) Development, 125, 88997

144. Millar CB, Guy J, Sansom OJ, Selfridge J, MacDougall E, Hendrich B, Keightley PD, Bishop SM, Clarke AR and Bird A, Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice (2002) Science, 297,403-5

145. Moore T and Haig D, Genomic imprinting in mammalian development: a parental tug-of-war (1991) Trends Genet, 7,45-9

146. Morgan HD, Dean W, Coker HA, Reik W and Petersen-Mahrt SK, Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming (2004) J Biol Chem, 279,52353-60

147. Nan X, Meehan RR and Bird A, Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2 (1993) Nucleic Acids Res, 21,4886-92

148. Nan X, Ng HH, Johnson CA, Laherty CD, Turner BM, Eisenman RN and Bird A, Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex (1998) Nature, 393,386-9

149. Narayan A, Ji W, Zhang XY, Marrogi A, Graff JR, Baylin SB and Ehrlich M, Hypomethylation of pericentromeric DNA in breast adenocarcinomas (1998) Int J Cancer, 77, 833-8

150. Negorev DG, Vladimirova OV, Ivanov A, Rauscher F, 3rd and Maul GG, Differential role of SplOO isoforms in interferon-mediated repression of herpes simplex virus type 1 immediate-early protein expression (2006) J Virol, 80,8019-29

151. Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D and Bird A, MBD2 is a transcriptional repressor belonging to the MeCPl histone deacetylase complex (1999) Nat Genet, 23,58-61

152. Ng HH, Jeppesen P and Bird A, Active repression of methylated genes by the chromosomal protein MBD1 (2000) Mol Cell Biol, 20,1394-406

153. Nguyen CT, Gonzales FA and Jones PA, Altered chromatin structure associated with methylation-induced gene silencing in cancer cells: correlation of accessibility, methylation, MeCP2 binding and acetylation (2001) Nucleic Acids Res, 29,4598-606

154. Nilsen H, Haushalter KA, Robins P, Barnes DE, Verdine GL and Lindahl T, Excision of deaminated cytosine from the vertebrate genome: role of the SMUG1 uracil-DNA glycosylase (2001) Embo J, 20,4278-86

155. Novak P, Jensen T, Oshiro MM, Wozniak RJ, Nouzova M, Watts GS, Klimecki WT, Kim С and Futscher BW, Epigenetic inactivation of the HOXA gene cluster in breast cancer (2006) Cancer Res, 66,10664-70

156. Nuber UA, Kriaucionis S, Roloff TC, Guy J, Selfridge J, Steinhoff C, Schulz R, Lipkowitz B, Ropers HH, Holmes MC and Bird A, Up-regulation of glucocorticoid-regulated genes in a mouse model of Rett syndrome (2005) Hum Mol Genet, 14,2247-56

157. Numata M, Ono T and Iseki S, Expression and localization of the mRNA for DNA (cytosine-5)- methyltransferase in mouse seminiferous tubules (1994) J Histochem Cytochem, 42,1271-6

158. Oakes CC, La Salle S, Smiraglia DJ, Robaire В and Trasler JM, Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells (2007) Dev Biol, 307, 368-379

159. Ohki I, Shimotake N, Fujita N, Nakao M and Shirakawa M, Solution structure of the methyl-CpG-binding domain of the methylation-dependent transcriptional repressor MBD11999) Embo J, 18,6653-61

160. Ohki I, Shimotake N, Fujita N, Jee J, Ikegami T, Nakao M and Shirakawa M, Solution structure of the methyl-CpG binding domain of human MBD1 in complex with methylated DNA (2001) Cell, 105,487-97

161. Okano M, Xie S and Li E, Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells (1998) Nucleic Acids Res, 26,2536-40

162. Okano M, Bell DW, Haber DA and Li E, DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development (1999) Cell, 99,247-57

163. Olek A, Oswald J and Walter J, A modified and improved method for bisulphite based cytosine methylation analysis (1996) Nucleic Acids Res, 24, 5064-6.

164. Orlando V, Mapping chromosomal proteins in vivo by formaldehyde-crosslinked-chromatin immunoprecipitation (2000) Trends Biochem Sci, 25,99-104

165. Palmisano WA, Divine KK, Saccomanno G, Gilliland FD, Baylin SB, Herman JG and Belinsky SA, Predicting lung cancer by detecting aberrant promoter methylation in sputum2000) Cancer Res, 60,5954-8

166. Paoloni-Giacobino A, D'Aiuto L, Cirio MC, Reinhart В and Chaillet JR, Conserved features of imprinted differentially methylated domains (2007) Gene,

167. Park JI, Kim SW, Lyons JP, Ji H, Nguyen TT, Cho K, Barton MC, Deroo T, Vleminckx K, Moon RT and McCrea PD, Kaiso/pl20-catenin and TCF/beta-catenin complexes coordinately regulate canonical Wnt gene targets (2005) Dev Cell, 8, 843-54

168. Paulsen M, El-Maarri O, Engemann S, Strodicke M, Franck O, Davies K, Reinhardt R, Reik W and Walter J, Sequence conservation and variability of imprinting in the Beckwith-Wiedemann syndrome gene cluster in human and mouse (2000) Hum Mol Genet, 9,1829-41

169. Pavlicek A, Jabbari K, Paces J, Paces V, Hejnar JV and Bernardi G, Similar integration but different stability of Alus and LINEs in the human genome (2001) Gene, 276, 39-45

170. Paz MF, Wei S, Cigudosa JC, Rodriguez-Perales S, Peinado MA, Huang TH and Esteller M, Genetic unmasking of epigenetically silenced tumor suppressor genes in colon cancer cells deficient in DNA methyltransferases (2003) Hum Mol Genet, 12, 2209-19

171. Ponger L, Duret L and Mouchiroud D, Determinants of CpG islands: expression in early embryo and isochore structure (2001) Genome Res, 11,1854-60

172. Posfai J, Bhagwat AS, Posfai G and Roberts RJ, Predictive motifs derived from cytosine methyltransferases (1989) Nucleic Acids Res, 17, 2421-35

173. Pradhan S and Esteve PO, Mammalian DNA (cytosine-5) methyltransferases and their expression (2003) Clin Immunol, 109,6-16

174. Prokhortchouk A, Hendrich B, Jorgensen H, Ruzov A, Wilm M, Georgiev G, Bird A and Prokhortchouk E, The pi20 catenin partner Kaiso is a DNA methylation-dependent transcriptional repressor (2001) Genes Dev, 15,1613-8

175. Pulukuri SM and Rao JS, CpG island promoter methylation and silencing of 14-3-3sigma gene expression in LNCaP and Tramp-Cl prostate cancer cell lines is associated with methyl-CpG-binding protein MBD2 (2006) Oncogene, 25,4559-72

176. Qiu C, Sawada K, Zhang X and Cheng X, The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds (2002) Nat Struct Biol, 9, 217-24

177. Qiu J, Epigenetics: unfinished symphony (2006) Nature, 441,143-5

178. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP and Jaenisch R, Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a (2000) Proc Natl Acad Sci USA, 97, 5237-42

179. Reik W and Walter J, Evolution of imprinting mechanisms: the battle of the sexes begins in the zygote (2001) Nat Genet, 27,255-6

180. Reik W and Walter J, Genomic imprinting: parental influence on the genome (2001) Nat Rev Genet, 2,21-32

181. Reik W, Santos F, Mitsuya K, Morgan H and Dean W, Epigenetic asymmetry in the mammalian zygote and early embryo: relationship to lineage commitment? (2003) Philos Trans R Soc Lond В Biol Sci, 358,1403-9; discussion 1409

182. Reik W, Stability and flexibility of epigenetic gene regulation in mammalian development (2007) Nature, 447,425-32

183. Reinhart B, Paoloni-Giacobino A and Chaillet JR, Specific differentially methylated domain sequences direct the maintenance of methylation at imprinted genes (2006) Mol Cell Biol, 26, 8347-56

184. Riggs AD, X inactivation, differentiation, and DNA methylation (1975) Cytogenet Cell Genet, 14,9-25

185. Ringrose L and Paro R, Epigenetic regulation of cellular memory by the Polycomb and Trithorax group proteins (2004) Annu Rev Genet, 38,413-43

186. Robertson KD, Uzvolgyi E, Liang G, Talmadge C, Sumegi J, Gonzales FA and Jones PA, The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors (1999) Nucleic Acids Res, 27,2291-8

187. Robertson KD, Ait-Si-Ali S, Yokochi T, Wade PA, Jones PL and Wolffe AP, DNMT1 forms a complex with Rb, E2F1 and HDAC1 and represses transcription from E2F-responsive promoters (2000) Nat Genet, 25, 338-42

188. Rodova M, Kelly KF, VanSaun M, Daniel JM and Werle MJ, Regulation of the rapsyn promoter by kaiso and delta-catenin (2004) Mol Cell Biol, 24, 7188-96

189. Roh TY, Cuddapah S and Zhao K, Active chromatin domains are defined by acetylation islands revealed by genome-wide mapping (2005) Genes Dev, 19,542-52

190. Romanov GA and Vanyushin BF, Methylation of reiterated sequences in mammalian DNAs. Effects of the tissue type, age, malignancy and hormonal induction (1981) Biochim Biophys Acta, 653, 204-18

191. Rountree MR, Bachman KE and Baylin SB, DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci (2000) Nat Genet, 25,269-77

192. Ruzov A, Dunican DS, Prokhortchouk A, Pennings S, Stancheva I, Prokhortchouk E and Meehan RR, Kaiso is a genome-wide repressor of transcription that is essential for amphibian development (2004) Development, 131,6185-94

193. Salinas J, Matassi G, Montero LM and Bernardi G, Compositional compartmentalization and compositional patterns in the nuclear genomes of plants (1988) Nucleic Acids Res, 16,426985

194. Sansom OJ, Berger J, Bishop SM, Hendrich B, Bird A and Clarke AR, Deficiency of Mbd2 suppresses intestinal tumorigenesis (2003) Nat Genet, 34,145-7

195. Santos F, Hendrich B, Reik W and Dean W, Dynamic reprogramming of DNA methylation in the early mouse embryo (2002) Dev Biol, 241,172-82

196. Santos F, Zakhartchenko V, Stojkovic M, Peters A, Jenuwein T, Wolf E, Reik W and Dean W, Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos (2003) Curr Biol, 13,1116-21

197. Santos F and Dean W, Epigenetic reprogramming during early development in mammals (2004) Reproduction, 127,643-51

198. Sarraf SA and Stancheva I, Methyl-CpG binding protein MBD1 couples histone H3 methylation at lysine 9 by SETDB1 to DNA replication and chromatin assembly (2004) Mol Cell, 15,595-605

199. Schmid M, Haaf T and Grunert D, 5-Azacytidine-induced undercondensations in human chromosomes (1984) Hum Genet, 67,257-63

200. Shahbazian MD, Antalffy B, Armstrong DL and Zoghbi HY, Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation (2002) Hum Mol Genet, 11,115-24

201. Singer-Sam J, Robinson MO, Bellve AR, Simon MI and Riggs AD, Measurement by quantitative PCR of changes in HPRT, PGK-1, PGK-2, APRT, MTase, and Zfy gene transcripts during mouse spermatogenesis (1990) Nucleic Acids Res, 18,1255-9

202. Sleutels F, Zwart R and Barlow DP, The non-coding Air RNA is required for silencing autosomal imprinted genes (2002) Nature, 415, 810-3

203. Smallwood A, Esteve PO, Pradhan S and Carey M, Functional cooperation between HP1 and DNMT1 mediates gene silencing (2007) Genes Dev, 21,1169-78

204. Smith ZE and Higgs DR, The pattern of replication at a human telomeric region (16pl3.3): its relationship to chromosome structure and gene expression (1999) Hum Mol Genet, 8,1373-86

205. Soussi T, p53 alterations in human cancer: more questions than answers (2007) Oncogene, 26,2145-56

206. Stoger R, Kubicka P, Liu CG, Kafri T, Razin A, Cedar H and Barlow DP, Maternal-specific methylation of the imprinted mouse Igf2r locus identifies the expressed locus as carrying the imprinting signal (1993) Cell, 73,61-71

207. Suetake I, Shinozaki F, Miyagawa J, Takeshima H and Tajima S, DNMT3L stimulates the DNA methylation activity of Dnmt3a and Dnmt3b through a direct interaction (2004) J Biol Chem, 279,27816-23

208. Surani MA, Imprinting and the initiation of gene silencing in the germ line (1998) Cell, 93,309-12

209. Surani MA, Hayashi К and Hajkova P, Genetic and epigenetic regulators of pluripotency (2007) Cell, 128,747-62

210. Sutherland JE and Costa M, Epigenetics and the environment (2003) Ann N Y Acad Sci, 983,151-60

211. Suzuki H, Gabrielson E, Chen W, Anbazhagan R, van Engeland M, Weijenberg MP, Herman JG and Baylin SB, A genomic screen for genes upregulated by demethylation and histone deacetylase inhibition in human colorectal cancer (2002) Nat Genet, 31, 141-9

212. Takai D and Jones PA, Comprehensive analysis of CpG islands in human chromosomes 21 and 22 (2002) Proc Natl Acad Sci USA, 99,3740-5

213. Trasler JM, Alcivar AA, Hake LE, Bestor T and Hecht NB, DNA methyltransferase is developmentally expressed in replicating and non-replicating male germ cells (1992) Nucleic Acids Res, 20, 2541-5

214. Traynor J, Agarwal P, Lazzeroni L and Francke U, Gene expression patterns vary in clonal cell cultures from Rett syndrome females with eight different MECP2 mutations (2002) BMC Med Genet, 3,12

215. Tucker KL, Beard C, Dausmann J, Jackson-Grusby L, Laird PW, Lei H, Li E and Jaenisch R, Germ-line passage is required for establishment of methylation and expression patterns of imprinted but not of nonimprinted genes (1996) Genes Dev, 10,1008-20

216. Tudor M, Akbarian S, Chen RZ and Jaenisch R, Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain (2002) Proc Natl Acad Sci US A, 99,15536-41

217. Turek-Plewa J and Jagodzinski PP, The role of mammalian DNA methyltransferases in the regulation of gene expression (2005) Cell Mol Biol Lett, 10,631-47

218. Turker MS and Bestor TH, Formation of methylation patterns in the mammalian genome (1997) Mutat Res, 386, 119-30

219. Turner BM, Histone acetylation and an epigenetic code (2000) Bioessays, 22, 836-45

220. Turner BM, Defining an epigenetic code (2007) Nat Cell Biol, 9,2-6

221. Tweedie S, Ng HH, Barlow AL, Turner BM, Hendrich В and Bird A, Vestiges of a DNA methylation system in Drosophila melanogaster? (1999) Nat Genet, 23,389-90

222. Umlauf D, Goto Y, Cao R, Cerqueira F, Wagschal A, Zhang Y and Feil R, Imprinting along the Kcnql domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes (2004) Nat Genet, 36,1296-300

223. Upham B, Weisb L, Rummelc A, Mastenb S and Troskoa J, The Effects of Anthracene and Methylated Anthracenes on Gap Junctional Intercellular Communication in Rat Liver Epithelial Cells. (2005) Fundam Appl Toxicol, 34,260-4

224. Ushijima T, Nakajima T and Maekita T, DNA methylation as a marker for the past and future (2006) J Gastroenterol, 41,401-7

225. Vaniushin BF, DNA methylation and epigenetics. (2006) Genetika, 42,1186-99

226. Vanyushin BF and Fais D, The nucleotide composition and ribonucleic and deoxyribonucleic acid content of some plant pollens (1962) Biokhimiia, 26,895-9

227. Vanyushin BF, Mazin AL, Vasilyev VK and Belozersky AN, The content of 5-methylcytosine in animal DNA: the species and tissue specificity (1973) Biochim Biophys Acta, 299,397-403

228. Waddington C, The Epigenotype. (1942) Endeavour, 1,18-20

229. Wade PA, Gegonne A, Jones PL, Ballestar E, Aubry F and Wolffe AP, Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation (1999) Nat Genet, 23, 62-6

230. Wade PA and Wolffe AP, ReCoGnizing methylated DNA (2001) Nat Struct Biol, 8, 5757

231. Wakefield RI, Smith BO, Nan X, Free A, Soteriou A, Uhrin D, Bird AP and Barlow PN, The solution structure of the domain from MeCP2 that binds to methylated DNA (1999) J Mol Biol, 291, 1055-65

232. Watanabe D, Suetake I, Tada T and Tajima S, Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis (2002) Mech Dev, 118,187-90

233. Waterland RA and Jirtle RL, Transposable elements: targets for early nutritional effects on epigenetic gene regulation (2003) Mol Cell Biol, 23,5293-300

234. Waterland RA, Lin JR, Smith CA and Jirtle RL, Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus (2006) Hum Mol Genet, 15, 705-16

235. Weaver 1С, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M and Meaney MJ, Epigenetic programming by maternal behavior (2004) Nat Neurosci, 7, 847-54

236. Weber M, Davies JJ, Wittig D, Oakeley EJ, Haase M, Lam WL and Schubeler D, Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells (2005) Nat Genet, 37, 853-62

237. Weber M, Hellmann I, Stadler MB, Ramos L, Paabo S, Rebhan M and Schubeler D, Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome (2007) Nat Genet, 39,457-66

238. Weitzel JM, Buhrmester H and Stratling WH, Chicken MAR-binding protein ARBP is homologous to rat methyl-CpG-binding protein MeCP2 (1997) Mol Cell Biol, 17, 5656-66

239. Widschwendter M, Jiang G, Woods C, Muller HM, Fiegl H, Goebel G, Marth C, Muller-Holzner E, Zeimet AG, Laird PW and Ehrlich M, DNA hypomethylation and ovarian cancer biology (2004) Cancer Res, 64,4472-80

240. Wilson AS, Power BE and Molloy PL, DNA hypomethylation and human diseases (2007) Biochim Biophys Acta, 1775,138-62

241. Wu J, Wang SH, Potter D, Liu JC, Smith LT, Wu YZ, Huang TH and Plass C, Diverse histone modifications on histone 3 lysine 9 and their relation to DNA methylation in specifying gene silencing (2007) BMC Genomics, 8,131

242. Xie S, Wang Z, Okano M, Nogami M, Li Y, He WW, Okumura К and Li E, Cloning, expression and chromosome locations of the human DNMT3 gene family (1999) Gene, 236, 8795

243. Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ and Viegas-Pequignot E, Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene (1999) Nature, 402,187-91

244. Yang XJ, Lysine acetylation and the bromodomain: a new partnership for signaling (2004) Bioessays, 26,1076-87

245. Yoder JA, Walsh CP and Bestor TH, Cytosine methylation and the ecology of intragenomic parasites (1997) Trends Genet, 13, 335-40

246. Yoder JA and Bestor TH, A candidate mammalian DNA methyltransferase related to pmtlp of fission yeast (1998) Hum Mol Genet, 7,279-84

247. Yoon HG, Chan DW, Reynolds AB, Qin J and Wong J, N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso (2003) Mol Cell, 12, 723-34

248. Zhang Y, Ng HH, Erdjument-Bromage H, Tempst P, Bird A and Reinberg D, Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation (1999) Genes Dev, 13,1924-35

249. Zhu J and Yao X, Use of DNA methylation for cancer detection and molecularclassification (2007) J Biochem Mol Biol, 40, 135-41