mesЭкстремальная биомедицинаExtreme Medicine3033-89643033-8972Centre for Strategic Planning of the Federal Medical and Biological Agency10.47183/mes.2021.003mes-106Research ArticleОБЗОРREVIEWАктуальные методы анализа изменений эпигенетического ландшафта организма, вызванных воздействием загрязнителей окружающей средыModern methods for analysis of changes to epigenetic landscape caused by exposure to environmental pollutantsЗаняткинИ. А.ZanyatkinI. A.

Иван Андреевич Заняткин

ул. Щукинская, д. 5, стр. 6, комн. 323, г. Москва, 123182

Ivan A. Zanyatkin

Shchukinskaya, 5, str. 6, k. 323, Moscow, 123182

izanyatkin@cspmz.ruТитоваА. Г.TitovaA. G.

г. Москва

Moscow

БаёвA. B.BayovA. V.

г. Москва

Moscow

Центр стратегического планирования и управления медико-биологическими рисками здоровью Федерального медико-биологического агентстваРоссияCentre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical Biological AgencyRussian Federation2021241020242313947Copyright © Заняткин И.А., Титова А.Г., Баёв A.B., 20242024Заняткин И.А., Титова А.Г., Баёв A.B.Zanyatkin I.A., Titova A.G., Bayov A.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.extrememedicine.ru/jour/article/view/106

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.

The diagnosis and treatment of diseases caused by the exposure of human epigenome to environmental pollutants are hampered by epigenomic plasticity, instability and nonlinear cumulative effects of existing transcriptional regulatory pathways. DNA methylation, histone acetylation and histone methylation are the best studied epigenetic modifications. There are simple methods for assessing genome-wide DNA methylation; however, it is essential to study the epigenetic landscape in detail in order to uncover the mechanisms underlying pollutant-associated effects on the organism. This prompts researchers to employ whole-genome sequencing and analyze vast arrays of sequencing data that can be compiled into extensive databases of human and animal epigenomes. Drugs developed to counter epigenetic disorders neutralize their symptoms and either affect epigenetic modifications across the entire genome or regulate the activity of enzymes that play a critical role in such disorders. Promise is held by targeted genome editing methods supported by modern technologies that are undergoing preclinical trials. This review discusses the potential of modern science in the diagnosis and treatment of diseases caused by environmental pollutants.

эпигенетические сигнатурыметилированиеацетилированиетоксическое воздействиеполлютантхронические заболеваниясеквенированиередактирование геномаface transplantmicrosurgeryfacial flapcomposite flapReferencesHiragami-Hamada K, et al. The molecular basis for stability of heterochromatin-mediated silencing in mammals. Epigenetics Chromatin. 2009; 2 (1): 14.Hiragami-Hamada K, et al. The molecular basis for stability of heterochromatin-mediated silencing in mammals. Epigenetics Chromatin. 2009; 2 (1): 14.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.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.Hartley PD, Madhani HD. Mechanisms that Specify Promoter Nucleosome Location and Identity. Cell. 2009; 137 (3): 445–58.Hartley PD, Madhani HD. Mechanisms that Specify Promoter Nucleosome Location and Identity. Cell. 2009; 137 (3): 445–58.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.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.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.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.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.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.Beiter T, et al. Antisense transcription: A critical look in both directions. Cell Mol Life Sci. 2009 Jan; 66 (1): 94–112.Beiter T, et al. Antisense transcription: A critical look in both directions. Cell Mol Life Sci. 2009 Jan; 66 (1): 94–112.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.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.Subramaniam D, et al. DNA Methyltransferases: A Novel Target for Prevention and Therapy. Front Oncol. 2014; 4: 80.Subramaniam D, et al. DNA Methyltransferases: A Novel Target for Prevention and Therapy. Front Oncol. 2014; 4: 80.Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature, 2013; 502 (7472): 472–79.Kohli RM, Zhang Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature, 2013; 502 (7472): 472–79.Gillette TG, Hill JA. Readers, writers, and erasers: Chromatin as the whiteboard of heart disease. Circulation Research. 2015; 116 (7): 1245–53.Gillette TG, Hill JA. Readers, writers, and erasers: Chromatin as the whiteboard of heart disease. Circulation Research. 2015; 116 (7): 1245–53.Софронов Г. А., Паткин Е. Л. Эпигенетическая токсикология: перспективы развития. Токсикологический вестник. 2018; 0 (1): 2–7.Sofronov GA, Patkin EL. Jepigeneticheskaja toksikologija: perspektivy razvitija. Toksikologicheskij vestnik. 2018; 0 (1): 2–7. Russian.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.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.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.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.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.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.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.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.Lister R, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009; 462 (7271): 315–22.Lister R, et al. Human DNA methylomes at base resolution show widespread epigenomic differences. Nature. 2009; 462 (7271): 315–22.Meissner A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature, 2008; 454 (7205): 766–70.Meissner A, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature, 2008; 454 (7205): 766–70.Suzuki M, et al. Optimized design and data analysis of tag-based cytosine methylation assays. Genome Biol. 2010; 1 (4): R36.Suzuki M, et al. Optimized design and data analysis of tag-based cytosine methylation assays. Genome Biol. 2010; 1 (4): R36.Ball MP et, al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009; 27 (4): 361–8.Ball MP et, al. Targeted and genome-scale strategies reveal gene-body methylation signatures in human cells. Nat Biotechnol. 2009; 27 (4): 361–8.Down TA, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008; 26 (7): 779–85.Down TA, et al. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008; 26 (7): 779–85.Bibikova M, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011; 98 (4): 288–95.Bibikova M, et al. High density DNA methylation array with single CpG site resolution. Genomics. 2011; 98 (4): 288–95.Nagalakshmi U, et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science. 2008; 320 (5881): 1344–9.Nagalakshmi U, et al. The transcriptional landscape of the yeast genome defined by RNA sequencing. Science. 2008; 320 (5881): 1344–9.Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007; 448 (7153): 553–60.Mikkelsen TS, et al. Genome-wide maps of chromatin state in pluripotent and lineage-committed cells. Nature. 2007; 448 (7153): 553–60.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.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.Fakhrai-Rad H, Pourmand N, Ronaghi M. PyrosequencingTM: An accurate detection platform for single nucleotide polymorphisms. Human Mutation. 2002; 19 (5): 479–85.Fakhrai-Rad H, Pourmand N, Ronaghi M. PyrosequencingTM: An accurate detection platform for single nucleotide polymorphisms. Human Mutation. 2002; 19 (5): 479–85.De Bustos C, et al. Tissue-specific variation in DNA methylation levels along human chromosome 1. Epigenetics Chromatin. 2009; 2 (1): 7.De Bustos C, et al. Tissue-specific variation in DNA methylation levels along human chromosome 1. Epigenetics Chromatin. 2009; 2 (1): 7.Christensen BC, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CPG island context. PLoS Genet. 2009; 5 (8): e1000602.Christensen BC, et al. Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CPG island context. PLoS Genet. 2009; 5 (8): e1000602.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.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.Peters AH, et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet. 2002; 30 (1): 77–80.Peters AH, et al. Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin. Nat Genet. 2002; 30 (1): 77–80.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.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.Tilgner H. et al. Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol. 2009; 16 (9): 996–1001.Tilgner H. et al. Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol. 2009; 16 (9): 996–1001.Laurent L, et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010; 20 (3): 320–31.Laurent L, et al. Dynamic changes in the human methylome during differentiation. Genome Res. 2010; 20 (3): 320–31.Hou Lifang, et al. Environmental Chemical Exposures and Human Epigenetics. Int J Epidemiol. 2012; 41 (1): 79–105.Hou Lifang, et al. Environmental Chemical Exposures and Human Epigenetics. Int J Epidemiol. 2012; 41 (1): 79–105.Simmons R. Perinatal Programming of Obesity. Semin Perinatol. 2008; 32 (5): 371–4.Simmons R. Perinatal Programming of Obesity. Semin Perinatol. 2008; 32 (5): 371–4.Gluckman PD, Hanson MA. Living with the past: Evolution, development, and patterns of disease. Science. 2004; 305 (691): 1733–6.Gluckman PD, Hanson MA. Living with the past: Evolution, development, and patterns of disease. Science. 2004; 305 (691): 1733–6.Derghal A, et al. An emerging role of micro-RNA in the effect of the endocrine disruptors. Front Neurosci. 2016; 10: 318.Derghal A, et al. An emerging role of micro-RNA in the effect of the endocrine disruptors. Front Neurosci. 2016; 10: 318.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.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.Ernst J, Kellis M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol. 2010; 28 (8): 817–25.Ernst J, Kellis M. Discovery and characterization of chromatin states for systematic annotation of the human genome. Nat Biotechnol. 2010; 28 (8): 817–25.LeBaron MJ, et al. Epigenetics and chemical safety assessment. Mutat Res. 2010; 705 (2): 83–95.LeBaron MJ, et al. Epigenetics and chemical safety assessment. Mutat Res. 2010; 705 (2): 83–95.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.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.Wild L, et al. In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation. Carcinogenesis. 2010; 31(10): 1854–62.Wild L, et al. In vitro transformation of mesenchymal stem cells induces gradual genomic hypomethylation. Carcinogenesis. 2010; 31(10): 1854–62.He Y, et al. Spatiotemporal DNA methylome dynamics of the developing mouse fetus: 7818. Nature. 2020; 583 (7818): 752–9.He Y, et al. Spatiotemporal DNA methylome dynamics of the developing mouse fetus: 7818. Nature. 2020; 583 (7818): 752–9.Anway M, Cupp A, Uzumcu M. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science. 2005; 308 (5727): 1466–9.Anway M, Cupp A, Uzumcu M. Epigenetic Transgenerational Actions of Endocrine Disruptors and Male Fertility. Science. 2005; 308 (5727): 1466–9.Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology. 2006; 147 (6 Suppl): S43–9.Anway MD, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors. Endocrinology. 2006; 147 (6 Suppl): S43–9.Crews D, et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA. 2007; 104 (14): 5942–6.Crews D, et al. Transgenerational epigenetic imprints on mate preference. Proc Natl Acad Sci USA. 2007; 104 (14): 5942–6.Guerrero-Bosagna CM, Skinner MK. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med. 2009; 27 (5): 403–8.Guerrero-Bosagna CM, Skinner MK. Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Semin Reprod Med. 2009; 27 (5): 403–8.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.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.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.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.Udvadia AJ, Linney E. Windows into development: Historic, current, and future perspectives on transgenic zebrafish. Dev Biol. 2003; 256 (1): 1–17.Udvadia AJ, Linney E. Windows into development: Historic, current, and future perspectives on transgenic zebrafish. Dev Biol. 2003; 256 (1): 1–17.Krauss V, Reuter G. DNA Methylation in drosophila-a critical evaluation. Prog Mol Biol Transl Sci. 2011; 101: 177–91.Krauss V, Reuter G. DNA Methylation in drosophila-a critical evaluation. Prog Mol Biol Transl Sci. 2011; 101: 177–91.Se K, et al. Sperm Epimutation Biomarkers of Obesity and Pathologies Following DDT Induced Epigenetic Transgenerational Inheritance of Disease. Environ Epigenet. 2019; 5 (2): dvz008Se K, et al. Sperm Epimutation Biomarkers of Obesity and Pathologies Following DDT Induced Epigenetic Transgenerational Inheritance of Disease. Environ Epigenet. 2019; 5 (2): dvz008Скрябин Н. А. и др. Методы исследования метилирования ДНК: возможности и перспективы использования в онкологии. Сибирский Онкологический Журнал. 2013; 6.Skrjabin NA, i dr. Metody issledovanija metilirovanija DNK: vozmozhnosti i perspektivy ispol'zovanija v onkologii. Sibirskij Onkologicheskij Zhurnal. 2013; 6. Russian.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.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.Fang M, Chen D, Yang CS. Dietary Polyphenols May Affect DNA Methylation. J Nutr. 2007; 137 (1 Suppl): 223S–228S.Fang M, Chen D, Yang CS. Dietary Polyphenols May Affect DNA Methylation. J Nutr. 2007; 137 (1 Suppl): 223S–228S.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.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.Gao Z, et al. Promoter demethylation of WIF-1 by epigallocatechin- 3-gallate in lung cancer cells. Anticancer Res. 2009; 29 (6): 2025–30.Gao Z, et al. Promoter demethylation of WIF-1 by epigallocatechin- 3-gallate in lung cancer cells. Anticancer Res. 2009; 29 (6): 2025–30.FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma. Oncologist. 2007; 12 (10): 1247–52.FDA Approval Summary: Vorinostat for Treatment of Advanced Primary Cutaneous T-Cell Lymphoma. Oncologist. 2007; 12 (10): 1247–52.Bubna AK. Vorinostat — An Overview. Indian J Dermatol. 2015; 60 (4): 419.Bubna AK. Vorinostat — An Overview. Indian J Dermatol. 2015; 60 (4): 419.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.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.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.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.Rajendran P, et al. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenetic. 2011; 3 (1): 4.Rajendran P, et al. Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells. Clin Epigenetic. 2011; 3 (1): 4.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.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.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.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.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.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.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.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.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.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.Campbell CT, et al. Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia. Mol Cancer Ther. 2017; 16 (8): 1669–79.Campbell CT, et al. Mechanisms of Pinometostat (EPZ-5676) Treatment–Emergent Resistance in MLL-Rearranged Leukemia. Mol Cancer Ther. 2017; 16 (8): 1669–79.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.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.Claus R, Lübbert M. Epigenetic targets in hematopoietic malignancies. Oncogene. 2003; 22 (42): 6489–96.Claus R, Lübbert M. Epigenetic targets in hematopoietic malignancies. Oncogene. 2003; 22 (42): 6489–96.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.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.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.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.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.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.

The authors declare that there are no conflicts of interest present.