Актуальные методы анализа изменений эпигенетического ландшафта организма, вызванных воздействием загрязнителей окружающей среды

Диагностика и лечение заболеваний, вызванных воздействием поллютантов на эпигеном человека, затруднены пластичностью и нестабильностью эпигенома, наличием нескольких путей регуляции транскрипции с нелинейной суммацией эффектов. Наиболее исследованные пути — метилирование ДНК, ацетилирование и метилирование гистонов. Доступны простые способы оценки уровня глобального метилирования ДНК, однако для определения механизмов воздействия загрязнителя на организм необходимо изучать эпигенетический ландшафт в деталях. Это заставляет ученых применять методы полногеномного секвенирования и обрабатывать огромные массивы результатов, что привело к появлению нескольких баз данных эпигенома человека и животных. Препараты для лечения эпигенетических нарушений сосредоточены на симптоматическом лечении и действуют на глобальное редактирование эпигенома или на регуляцию активности ферментов, играющих критическую роль в нарушении. Более перспективны методы селективного эпигеномного редактирования, основанные на абсолютно новых технологиях, находящихся на стадии лабораторных исследований. Представлен обзор современных возможностей науки в области диагностики и лечения заболеваний, вызванных воздействием поллютантов на эпигеном человека.

1. Hiragami-Hamada K, et al. The molecular basis for stability of heterochromatin-mediated silencing in mammals. Epigenetics Chromatin. 2009; 2 (1): 14.

2. Bernstein E, et al. A phosphorylated subpopulation of the histone variant macroH2A1 is excluded from the inactive X chromosome and enriched during mitosis. Proc Natl Acad Sci USA. 2008 Feb 5; 105 (5): 1533–8.

3. Hartley PD, Madhani HD. Mechanisms that Specify Promoter Nucleosome Location and Identity. Cell. 2009; 137 (3): 445–58.

4. Jing H, et al. Exchange of GATA Factors Mediates Transitions in Looped Chromatin Organization at a Developmentally Regulated Gene Locus. Molecular Cell. 2008; 29 (2): 232–42.

5. Klose RJ, Bird AP. Genomic DNA methylation: The mark and its mediators. Trends in Biochemical Sciences. 2006. DOI: 10.1016/J.TIBS.2005.12.008.

6. Roy D, Yu K, Lieber MR. Mechanism of R-Loop Formation at Immunoglobulin Class Switch Sequences. Mol Cell Biol. 2008 Jan; 28 (1): 50–60.

7. Beiter T, et al. Antisense transcription: A critical look in both directions. Cell Mol Life Sci. 2009 Jan; 66 (1): 94–112.

8. Gore AC, et al. EDC-2: The Endocrine Society’s Second Scientific Statement on Endocrine-Disrupting Chemicals. Endocrine Reviews. Endocrine Society. 2015; 36 (6): 1–150.

9. Subramaniam D, et al. DNA Methyltransferases: A Novel Target for Prevention and Therapy. Front Oncol. 2014; 4: 80.

10. Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature, 2013; 502 (7472): 472–79.

11. Gillette TG, Hill JA. Readers, writers, and erasers: Chromatin as the whiteboard of heart disease. Circulation Research. 2015; 116 (7): 1245–53.

12. Софронов Г. А., Паткин Е. Л. Эпигенетическая токсикология: перспективы развития. Токсикологический вестник. 2018; 0 (1): 2–7.

13. Anglim PP, et al. Identification of a panel of sensitive and specific DNA methylation markers for squamous cell lung cancer. Mol Cancer. 2008; 7: 62.

14. Hooven LA, Baird WM. Proteomic analysis of MCF-7 cells treated with benzo[a]pyrene, dibenzo[a,l]pyrene, coal tar extract, and diesel exhaust extract. Toxicology. 2008; 249 (1): 1–10.

15. Méplan C, Mann K, Hainaut P. Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem. 1999; 274 (44): 31663–70.

16. Thompson RF, et al. Experimental intrauterine growth restriction induces alterations in DNA methylation and gene expression in pancreatic islets of rats. J Biol Chem. 2010; 285 (20): 15111–8.

17. Lister R, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009; 462 (7271): 315–22.

18. Meissner A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature, 2008; 454 (7205): 766–70.

19. Suzuki M, et al. Optimized design and data analysis of tag-based cytosine methylation assays. Genome Biol. 2010; 1 (4): R36.

20. Ball MP et, al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009; 27 (4): 361–8.

21. Down TA, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008; 26 (7): 779–85.

22. Bibikova M, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011; 98 (4): 288–95.

23. Nagalakshmi U, et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science. 2008; 320 (5881): 1344–9.

24. Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007; 448 (7153): 553–60.

25. Song L, Crawford GE. DNase-seq: A high-resolution technique for mapping active gene regulatory elements across the genome from mammalian cells. Cold Spring Harb Protoc. 2010; 5 (2): pdb. prot5384.

26. Fakhrai-Rad H, Pourmand N, Ronaghi M. PyrosequencingTM: An accurate detection platform for single nucleotide polymorphisms. Human Mutation. 2002; 19 (5): 479–85.

27. De Bustos C, et al. Tissue-specific variation in DNA methylation levels along human chromosome 1. Epigenetics Chromatin. 2009; 2 (1): 7.

28. Christensen BC, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CPG island context. PLoS Genet. 2009; 5 (8): e1000602.

29. Ma X, Chen J, Tian Y. Pregnane X receptor as the sensor and effector in regulating epigenome. J Cell Physiol. 2015; 230 (4): 752–7.

30. Peters AH, et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet. 2002; 30 (1): 77–80.

31. Vakoc CR, et al. Histone H3 lysine 9 methylation and HP1γ are associated with transcription elongation through mammalian chromatin. Mol Cell. 2005; 19 (3): 381–91.

32. Tilgner H. et al. Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol. 2009; 16 (9): 996–1001.

33. Laurent L, et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010; 20 (3): 320–31.

34. Hou Lifang, et al. Environmental Chemical Exposures and Human Epigenetics. Int J Epidemiol. 2012; 41 (1): 79–105.

35. Simmons R. Perinatal Programming of Obesity. Semin Perinatol. 2008; 32 (5): 371–4.

36. Gluckman PD, Hanson MA. Living with the past: Evolution, development, and patterns of disease. Science. 2004; 305 (691): 1733–6.

37. Derghal A, et al. An emerging role of micro-RNA in the effect of the endocrine disruptors. Front Neurosci. 2016; 10: 318.

38. Doherty LF, et al. In utero exposure to diethylstilbestrol (DES) or bisphenol-A (BPA) increases EZH2 expression in the mammary gland: An epigenetic mechanism linking endocrine disruptors to breast cancer. Horm Cancer. 2010; 1 (3): 146–55.

39. Ernst J, Kellis M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol. 2010; 28 (8): 817–25.

40. LeBaron MJ, et al. Epigenetics and chemical safety assessment. Mutat Res. 2010; 705 (2): 83–95.

41. Jay IG, et al. What Do We Need to Know Prior to Thinking About Incorporating an Epigenetic Evaluation Into Safety Assessments? Toxicol Sci. 2010; 116 (2): 375–81.

42. Wild L, et al. In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation. Carcinogenesis. 2010; 31(10): 1854–62.

43. He Y, et al. Spatiotemporal DNA methylome dynamics of the developing mouse fetus: 7818. Nature. 2020; 583 (7818): 752–9.

44. Anway M, Cupp A, Uzumcu M. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science. 2005; 308 (5727): 1466–9.

45. Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology. 2006; 147 (6 Suppl): S43–9.

46. Crews D, et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA. 2007; 104 (14): 5942–6.

47. Guerrero-Bosagna CM, Skinner MK. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med. 2009; 27 (5): 403–8.

48. Dolinoy DC, Huang D, Jirtle RL. Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethylation in early development. Proc Natl Acad Sci USA. 2007; 104 (32): 13056–61.

49. Rosenfeld CS, et al. Maternal exposure to bisphenol A and genistein has minimal effect on A vy/a offspring coat color but favors birth of agouti over nonagouti mice. Proc Natl Acad Sci USA. 2013: 110 (2): 537–42.

50. Udvadia AJ, Linney E. Windows into development: Historic, current, and future perspectives on transgenic zebrafish. Dev Biol. 2003; 256 (1): 1–17.

51. Krauss V, Reuter G. DNA Methylation in drosophila-a critical evaluation. Prog Mol Biol Transl Sci. 2011; 101: 177–91.

52. Se K, et al. Sperm Epimutation Biomarkers of Obesity and Pathologies Following DDT Induced Epigenetic Transgenerational Inheritance of Disease. Environ Epigenet. 2019; 5 (2): dvz008

53. Скрябин Н. А. и др. Методы исследования метилирования ДНК: возможности и перспективы использования в онкологии. Сибирский Онкологический Журнал. 2013; 6.

54. Pandey M, Shukla S, Gupta S. Promoter demethylation and chromatin remodeling by green tea polyphenols leads to re- expression of GSTP1 in human prostate cancer cells. Int J Cancer. 2010; 126 (11): 2520–33.

55. Fang M, Chen D, Yang CS. Dietary Polyphenols May Affect DNA Methylation. J Nutr. 2007; 137 (1 Suppl): 223S–228S.

56. Won JL, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol. 2005; 68 (4): 1018–30.

57. Gao Z, et al. Promoter demethylation of WIF-1 by epigallocatechin- 3-gallate in lung cancer cells. Anticancer Res. 2009; 29 (6): 2025–30.

58. FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma. Oncologist. 2007; 12 (10): 1247–52.

59. Bubna AK. Vorinostat — An Overview. Indian J Dermatol. 2015; 60 (4): 419.

60. Beaver LM, et al. 3,3’-Diindolylmethane, but not indole-3- carbinol, inhibits histone deacetylase activity in prostate cancer cells. Toxicol Appl Pharmacol. 2012; 263 (3): 345–51.

61. Goon P, Sonnex C, Jani P, et al. Recurrent respiratory papillomatosis: an overview of current thinking and treatment. Eur Arch Otorhinolaryngol. 2008; 265: 147–51.

62. Rajendran P, et al. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenetic. 2011; 3 (1): 4.

63. Zhang WW, Feng Z, Narod SA. Multiple therapeutic and preventive effects of 3,3′-diindolylmethane on cancers including prostate cancer and high grade prostatic intraepithelial neoplasia. J Biomed Res. 2014; 28 (5): 339–48.

64. Fan S, et al. DIM (3,3'-diindolylmethane) confers protection against ionizing radiation by a unique mechanism. Proc Natl Acad Sci USA. 2013; 110 (46): 18650–5.

65. Lyn-Cook BD, Mohammed SI, et al. Gender differences in gemcitabine (Gemzar) efficacy in cancer cells: effect of indole-3- carbinol. Anticancer Res. 2010; 30 (12): 4907–13.

66. Auborn KJ, et al. Lifespan Is Prolonged in Autoimmune-Prone (NZB/NZW) F1 Mice Fed a Diet Supplemented with Indole-3- Carbinol. J Nutr Oxford Academic. 2003; 133 (11): 3610–3.

67. Italiano A, et al. Tazemetostat, an EZH2 inhibitor, in relapsed or refractory B-cell non-Hodgkin lymphoma and advanced solid tumours: a first-in-human, open-label, phase 1 study. Lancet Oncol. 2018; 19 (5): 649–59.

68. Campbell CT, et al. Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia. Mol Cancer Ther. 2017; 16 (8): 1669–79.

69. Siu LL, Rasco DW, Vinay SP, et al. METEOR-1: a phase I study of GSK3326595, a first-in-class protein arginine methyltransferase 5 (PRMT5) inhibitor, in advanced solid tumours. Ann Oncol. 2019; 30 (Suppl 5): v159–v193.

70. Claus R, Lübbert M. Epigenetic targets in hematopoietic malignancies. Oncogene. 2003; 22 (42): 6489–96.

71. Pogribny IP, Tryndyak VP, Boureiko A, Melnyk S, Bagnyukova TV, Montgomery B, et al. Mechanisms of peroxisome proliferator- induced DNA hypomethylation in rat liver. Mutat Res. 2008; 644 (1–2): 17–23.

72. Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr. 2002; 132 (8 Suppl): 2333S–5S.

73. Verma S, et al. Computational approaches in epitope design using DNA binding proteins as vaccine candidate in Mycobacterium tuberculosis. Infect Genet Evol. 2020; 83: 1348–1567.