EPİGENETİK DEĞİŞİKLİK NEDİR VE HASTALIKLARIN MOLEKÜLER PATOLOJİK MEKANİZMALARI ÜZERİNDEKİ ETKİSİ HAKKINDA NE BİLİYORUZ?

Year 2022, , 273 - 283, 30.06.2022

Kemal Kürşat Bozkurt , Ayca Tan , Onur Ertunç , Rafet Güneş Öztürk , Yasemin Çakır , Zeynep Sağnak Yılmaz , Şadiye Ünlü

https://doi.org/10.17343/sdutfd.1090522

Abstract

Epigenetik değişiklik, kromatin modifikasyonu, DNA
metilasyonu, histon modifikasyonu, kromatin düzenleyici
proteinler ve kodlamayan RNA'lar yoluyla meydana
gelmekte olup, kalıcı genotipik değişiklik olmaksızın
gerçekleşen fenotipik bir değişikliği ifade eder.
Transkripsiyon sonrası m6A RNA metilasyonu da yeni
tanımlanmış bir epigenetik mekanizma olup, yeni bir
tanısal biyobelirteç ve potansiyel terapötik hedef olduğuna
inanılmaktadır. Epigenetik değişikliklerin birçok
nonneoplastik ve neoplastik hastalığın gelişiminde
ve ilerlemesinde önemli bir rol oynadığı iyi bilinen bir
gerçektir. Bu nedenle epigenetik değişiklikler tanısal
ve prognostik açıdan değerlidir. Öte yandan kişiselleştirilmiş
tıp ve hedefe yönelik tedavi yaklaşımlarının
gelişmesiyle birlikte epigenetik değişiklikleri hedefleyen
tedavi stratejileri birçok hastalık için umut verici
bir alan haline gelmektedir. Bu derlemenin amacı,
epigenetik değişikliklerin mekanizmaları ve neoplastik
/ nonneoplastik hastalıkların gelişimindeki rolleri hakkında
klinisyenlere ve laboratuvar tıbbı uzmanlarına
daha sonraki araştırmalar için yardımcı olabilecek bilgiler
sağlamaktır.

Keywords

epigenetik, hastalık, nonneoplastik, neoplastik

Supporting Institution

Herhangi bir destek alınmamıştır.

WHAT IS EPIGENETIC CHANGE AND WHAT DO WE KNOW ABOUT ITS IMPACT ON MOLECULAR PATHOLOGIC MECHANISMS OF THE DISEASES?

Abstract

Epigenetic change refers to a phenotypic alteration
without permanent genotypic change, which occurs
through chromatin modification, DNA methylation,
histone modification, chromatin-regulating proteins
and non-coding RNAs. Post-transcriptional m6A
RNA methylation is also a newly described epigenetic
mechanism and believed to be a new diagnostic
biomarker and potential therapeutic target. It is a well-
known fact that epigenetic changes play a significant
role in the development and progression of several
nonneoplastic and neoplastic diseases. Therefore,
epigenetic changes are of value in diagnostic
and prognostic terms. On the other hand, with the
development of personalized medicine and targeted
treatment approaches, treatment strategies targeting
the epigenetic changes are becoming a promising
area for many diseases. The aim of this review is
to provide information about the mechanisms of
epigenetic changes and their role in the development
of neoplastic and nonneoplastic diseases, which may
be helpful for the clinicians and laboratory medicine
experts for further researchs.

Keywords

epigenetic, disease, nonneoplastic, neoplastic

References

• Referans1. Cooper GM (Ed.). The cell: a molecular approach. Eighth edition. Oxford; New York: Sinauer Associates, an imprint of Oxford University Press; 2019. ISBN:9781605357461.
• Referans2. Carlberg C, Molnar F (Eds.). Human Epigenetics: How Science Works. Springer Nature Switzerland; 2019. ISBN:978-3-030-22907-8.
• Referans3. Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GHT, Wong AHC, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A. DNA Methylation Profiles in Monozygotic and Dizygotic Twins. Nat Genet 2009;41(2):240-245. DOI:10.1038/ng.286.
• Referans4. Zhang Y, Geng X, Li Q, Xu J, Tan Y, Xiao M, Song J, Liu F, Fang C, Wang H. m6A modification in RNA: biogenesis, functions and roles in gliomas. J Exp Clin Cancer Res 2020;39:192. DOI:10.1186/s13046-020-01706-8.
• Referans5. Yang C, Hu Y, Zhou B, Bao Y, Li Z, Gong C, Yang H, Wang S, Xiao Y. The role of m6A modification in physiology and disease. Cell Death Dis 2020;11:960. DOI:10.1038/s41419-020-03143-z.
• Referans6. Burns SN. Gene Expression, Epigenetic Regulation and Cancer. In: Bishnupuri KS, Mishra MK (Eds.). Epigenetic Advancements in Cancer. 1st ed. Cham: Springer International Publishing; 2016:79-94. ISBN:978-3-319-24951-3.
• Referans7. Lassi M, Teperino R. Introduction to Epigenetic Inheritance: Definition, Mechanisms, Implications and Relevance. In Teperino R (Ed.). Beyond Our Genes. Pathophysiology of Gene and Environment Interaction and Epigenetic Inheritance. Switzerland: Springer Nature AG, 2020:159-161. ISBN:978-3-030-35213-4.
• Referans8. Heard E, Martienssen RA. Transgenerational epigenetic inheritance: Myths and mechanisms. Cell 2014;157(1):95-109. DOI:10.1016/j.cell.2014.02.045.
• Referans9. Klemm SL, Shipony Z, Greenleaf WJ. Chromatin accessibility and the regulatory epigenome. Nat Rev Genet 2019;20(4):207-220. DOI:10.1038/s41576-018-0089-8.
• Referans10. Murakami Y. Heterochromatin and Euchromatin. In: Encyclopedia of Systems Biology. New York, NY: Springer New York; 2013:881-884. DOI:10.1007/978-1-4419-9863-7_1413.
• Referans11. Whalen S, Truty RM, Pollard KS. Enhancer–promoter interactions are encoded by complex genomic signatures on looping chromatin. Nat Genet 2016;48(5):488-496. DOI:10.1038/ng.3539.
• Referans12. Calo E, Wysocka J. Modification of Enhancer Chromatin: What, How, and Why? Mol Cell 2013;49(5):825-837. DOI:10.1016/j.molcel.2013.01.038.
• Referans13. Skvortsova K, Stirzaker C, Taberlay P. The DNA methylation landscape in cancer. Essays Biochem 2019;63(6):797-811. DOI:10.1042/EBC20190037.
• Referans14. Kanwal R, Gupta S. Epigenetic modifications in cancer. Clin Genet 2012;81(4):303-311. DOI:10.1111/j.1399-0004.2011.01809.x.
• Referans15. Camprubí C, Blanco J (Eds.). Epigenetics and assisted reproduction: an introductory guide. Boca Raton, FL: CRC Press/Taylor & Francis Group; 2019. ISBN:9781138633094.
• Referans16. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 2010;28(10):1057-1068. DOI:10.1038/nbt.1685.
• Referans17. Ferreira HJ, Esteller M. CpG Islands in Cancer: Heads, Tails, and Sides. Methods Mol Biol 2018;1766:49-80. DOI:10.1007/978-1-4939-7768-0_4.
• Referans18. Radford EJ. An Introduction to Epigenetic Mechanisms. Prog Mol Biol Transl Sci Prog Mol Biol Transl Sci 2018;158:29-48. DOI:10.1016/bs.pmbts.2018.04.002.
• Referans19. Hesson LB, Pritchard AL (Eds.). Clinical Epigenetics. Singapore: Springer Singapore; 2019. ISBN:978-981-13-8958-0.
• Referans20. Steunou AL, Rossetto D, Côté J. Regulating chromatin by histone acetylation. In: Workman JL, Abmayr SM (eds.). Fundamentals of chromatin. Springer, New York, NY; 2014:147-212. ISBN:978-1-4614-8624-4.
• Referans21. Chang B, Chen Y, Zhao Y, Bruick RK. JMJD6 is a histone arginine demethylase. Science 2007;318:444-447. DOI:10.1126/science.1145801.
• Referans22. Di Cerbo V, Mohn F, Ryan DP, Montellier E, Kacem S, Tropberger P, Kallis E, Holzner M, Hoerner L, Feldmann A, Richter FM, Bannister AJ, Mittler G, Michaelis J, Khochbin S, Feil R, Schuebeler D, Owen-Hughes T, Daujat S, Schneider R. Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription. eLife 2014;3:e01632. DOI:10.7554/eLife.01632.
• Referans23. Xhemalce B, Dawson MA, Bannister AJ. Histone modifications. In: Meyers R (ed.). Encyclopedia of Molecular Cell Biology and Molecular Medicine. John Wiley and Sons, 2011. ISBN:978-3527306534.
• Referans24. Mazzone R, Zwergel C, Artico M, Taurone S, Ralli M, Greco A, Mai A. The emerging role of epigenetics in human autoimmune disorders. Clin Epigenetics 2019;11:34. DOI:10.1186/s13148-019-0632-2.
• Referans25. Dykes IM, Emanueli C. Transcriptional and Post-transcriptional Gene Regulation by Long Non-coding RNA. Genom Proteom Bioinf 2017;15:177-186. DOI:10.1016/j.gpb.2016.12.005.
• Referans26. Panni S, Lovering RC, Porras P, Orchard S. Non-coding RNA regulatory networks. BBA - Gene Regulatory Mechanisms 2020;1863(6):194417. DOI:10.1016/j.bbagrm.2019.194417.
• Referans27. Chen QW, Zhu XY, Li YY, Meng ZQ. Epigenetic regulation and cancer (Review). Oncol Rep 2014;31:523-532. DOI:10.3892/or.2013.2913.
• Referans28. Wei JW, Huang K, Yang C, Kang CS. Non-coding RNAs as regulators in epigenetics (Review). Oncol Rep 2017;37:3-9. DOI:10.3892/or.2016.5236.
• Referans29. Neidhart M (Ed.). DNA Methylation and Complex Human Disease. Translational Epigenetics. San Diego, CA, 2015: Academic Press. ISBN:9780127999203.
• Referans30. Lovrečić L, Maver A, Zadel M, Peterlin B. The Role of Epigenetics in Neurodegenerative Diseases In: Uday K (Ed.). Neurodegenerative Diseases. Rijeka, 2013: IntechOpen. DOI:10.5772/45957.
• Referans31. Xylaki M, Atzler B, Outeiro TF. Epigenetics of the Synapse in Neurodegeneration. Curr Neurol Neurosci Rep 2019;19(10):72. DOI:10.1007/s11910-019-0995-y.
• Referans32. Moosavi A, Ardekani AM. Role of Epigenetics in Biology and Human Diseases. Iran Biomed J 2016;20(5):246-258. DOI:10.22045/ibj.2016.01.
• Referans33. Zhang Z, Zhang R. Epigenetics in autoimmune diseases: Pathogenesis and prospects for therapy. Autoimmun Rev 2015;14(10):854-63. DOI:10.1016/j.autrev.2015.05.008.
• Referans34. Quintero-Ronderos P, Montoya-Ortiz G. Epigenetics and Autoimmune Diseases. Autoimmune Dis 2012;2012:593720. DOI:10.1155/2012/593720.
• Referans35. Musse AA, Boggs JM, Harauz G. Deimination of membrane-bound myelin basic protein in multiple sclerosis exposes an immunodominant epitope. Proc Natl Acad Sci 2006;103(12):4422-4427. DOI:10.1073/pnas.0509158103.
• Referans36. Roggli E, Britan A, Gattesco S, Lin-Marq N, Abderrahmani A, Meda P, Regazzi R. Involvement of MicroRNAs in the Cytotoxic Effects Exerted by Proinflammatory Cytokines on Pancreatic - Cells. Diabetes 2010;59(4):978-986. DOI:10.2337/db09-0881.
• Referans37. Lovinsky-Desir S, Miller RL. Epigenetics, asthma, and allergic diseases: A review of the latest advancements. Curr Allergy Asthma Rep 2012;12(3):211-220. DOI:10.1007/s11882-012-0257-4.
• Referans38. Kundakovic M. Epigenetics of Psychiatric Disorders. In: Grayson D (Ed.). Medical Epigenetics. Elsevier; 2016:335-350. ISBN:9780128135662.
• Referans39. McGowan PO, Sasaki A, D’Alessio AC, Dymov S, Labonté B, Szyf M, Turecki G, Meaney MJ. Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse. Nat Neurosci 2009;12(3):342-348. DOI:10.1038/nn.2270.
• Referans40. Huang H-S, Matevossian A, Whittle C, Kim SY, Schumacher A, Baker SP, Akbarian S. Prefrontal Dysfunction in Schizophrenia Involves Mixed-Lineage Leukemia 1-Regulated Histone Methylation at GABAergic Gene Promoters. J Neurosci 2007;27(42):11254-11262. DOI:10.1523/JNEUROSCI.3272-07.2007.
• Referans41. Luo J, Qu J, Wu DK, Lu ZL, Sun YS, Qu Q. Long non-coding RNAs: a rising biotarget in colorectal cancer. Oncotarget 2017;8(13):22187-22202. DOI:10.18632/oncotarget.14728.
• Referans42. Pussila M, Törönen P, Einarsdottir E, Katayama S, Krjutškov K, Holm L, Kere J, Peltomäki P, Mäkinen MJ, Linden J, Nyström M. Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer. Carcinogenesis 2018;39(6):788-797. DOI:10.1093/carcin/bgy056.
• Referans43. Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 2020;17(2):111-130. DOI:10.1038/s41575-019-0230-y.
• Referans44. Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: The gastric cancer epigenome. Nat Rev Gastroenterol Hepatol 2017;14:467-478. DOI:10.1038/nrgastro.2017.53.
• Referans45. Liu H, Zhang Q, Lou Q, Zhang X, Cui Y, Wang P, Yang F, Wu F, Wang J, Fan T, Li S. Differential Analysis of lncRNA, miRNA and mRNA Expression Profiles and the Prognostic Value of lncRNA in Esophageal Cancer. Pathol Oncol Res 2020;26:1029-1039. DOI:10.1007/s12253-019-00655-8.
• Referans46. Guo M, House MG, Suzuki H, Ye Y, Brock MV, Lu F, Liu Z, Rustgi AK, Herman JG. Epigenetic silencing of CDX2 is a feature of squamous esophageal cancer. Int J Cancer 2007;121:1219-1226. DOI:10.1002/ijc.22828.
• Referans47. Karajannis MA, Zagzag D (Eds.). Molecular Pathology of Nervous System Tumors: Biological Stratification and Targeted Therapies [Internet]. New York, NY: Springer New York; 2015. ISBN:978-1-4939-1830-0.
• Referans48. Dubuc AM, Mack S, Unterberger A, Northcott PA, Taylor MD. The Epigenetics of Brain Tumors. Methods Mol Biol 2012;863:139-153. DOI:10.1007/978-1-61779-612-8_8.
• Referans49. Suter RK, Rodriguez-Blanco J, Ayad NG. Epigenetic pathways and plasticity in brain tumors. Neurobiol Dis 2020;145:105060. DOI:10.1016/j.nbd.2020.105060.
• Referans50. Rodríguez-Rodero S, Delgado-Álvarez E, Díaz-Naya L, Nieto AM, Torre EM. Epigenetic modulators of thyroid cancer. Endocrinol Diabetes Nutr 2017;64(1):44-56. DOI:10.1016/j.endinu.2016.09.006.
• Referans51. Asa SL, Ezzat S. The epigenetic landscape of differentiated thyroid cancer. Mol Cell Endocrinol 2018;469:3-10. DOI:10.1016/j.mce.2017.07.012.
• Referans52. Ahmed AA, Essa MEA. Potential of epigenetic events in human thyroid cancer. Cancer Genet 2019;239:13-21. DOI:10.1016/j.cancergen.2019.08.006.
• Referans53. Catalano MG, Fortunati N, Boccuzzi G. Epigenetics Modifications and Therapeutic Prospects in Human Thyroid Cancer. Front Endocrinol 2012;3:40. DOI:10.3389/fendo.2012.00040.
• Referans54. Guo W, Xu T, Lee JJ, Murphy GF, Lian CG. Epigenetic markers in melanoma. Melanoma Manag 2015;2(4):367-382. DOI:10.2217/mmt.15.30.
• Referans55. Micevic G, Theodosakis N, Bosenberg M. Aberrant DNA methylation in melanoma: biomarker and therapeutic opportunities. Clin Epigenetics 2017;9:34. DOI:10.1186/s13148-017-0332-8.
• Referans56. Sarkar D, Leung EY, Baguley BC, Finlay GJ, Askarian-Amiri ME. Epigenetic regulation in human melanoma: past and future. Epigenetics 2015;10(2):103-121. DOI:10.1080/15592294.2014.1003746.
• Referans57. Mannavola F, D’Oronzo S, Cives M, Stucci LS, Ranieri G, Silvestris F, Tucci M. Extracellular Vesicles and Epigenetic Modifications Are Hallmarks of Melanoma Progression. Int J Mol Sci 2019;21(1):52. DOI:10.3390/ijms21010052.
• Referans58. Ansari J, Shackelford RE, El-Osta H. Epigenetics in non-small cell lung cancer: from basics to therapeutics. Transl Lung Cancer Res 2016;5(2):155-171. DOI:10.21037/tlcr.2016.02.02.
• Referans59. Suzuki A, Makinoshima H, Wakaguri H, Esumi H, Sugano S, Kohno T, Tsuchihara K, Suzuki Y. Aberrant transcriptional regulations in cancers: genome, transcriptome and epigenome analysis of lung adenocarcinoma cell lines. Nucleic Acids Res 2014;42(22):13557-13572. DOI:10.1093/nar/gku885.
• Referans60. Vosa U, Vooder T, Kolde R, Vilo J, Metspalu A, Annilo T. Meta-analysis of microRNA expression in lung cancer. Int J Cancer 2013;132(12):2884-2893. DOI:10.1002/ijc.27981.
• Referans61. Wu X, Gao Y, Bu J, Deng L, Zhang P, Chi M, Jiang L, Shi X, Ning S, Wang G. Identification of Potential Long Non-coding RNA Expression Quantitative Trait Methylations in Lung Adenocarcinoma and Lung Squamous Carcinoma. Front Genet 2020;11:602035. DOI:10.3389/fgene.2020.602035.
• Referans62. Weeramange CE, Tang KD, Vasani S, Langton-Lockton J, Kenny L, Punyadeera C. DNA Methylation Changes in Human Papillomavirus-Driven Head and Neck Cancers. Cells 2020;9:1359. DOI:10.3390/cells9061359.
• Referans63. Le JM, Squarize CH, Castilho RM. Histone modifications: Targeting head and neck cancer stem cells. World J Stem Cells 2014;6(5):511-525. DOI:10.4252/wjsc.v6.i5.511.
• Referans64. Nowicka Z, Stawiski K, Tomasik B, Fendler W. Extracellular miRNAs as Biomarkers of Head and Neck Cancer Progression and Metastasis. Int J Mol Sci 2019;20:4799. DOI:10.3390/ijms20194799.
• Referans65. Wu Y, Sarkissyan M, Vadgama JV. Epigenetics in Breast and Prostate Cancer. Methods Mol Biol 2015;1238:425-466. DOI:10.1007/978-1-4939-1804-1_23.
• Referans66. Chen J, Luo Q, Yuan Y, Huang X, Cai W, Li C, Wei T, Zhang L, Yang M, Liu Q, Ye G, Dai X, Li B. Pygo2 associates with MLL2 histone methyltransferase and GCN5 histone acetyltransferase complexes to augment Wnt target gene expression and breast cancer stem-like cell expansion. Mol Cell Biol 2010;30:5621-5635. DOI:10.1128/MCB.00465-10.
• Referans67. Shi L, Sun L, Li Q, Liang J, Yu W, Yi X, Yang X, Li Y, Han X, Zhang Y, Xuan C, Yao Z, Shang Y. Histone demethylase JMJD2B coordinates H3K4/H3K9 methylation and promotes hormonally responsive breast carcinogenesis. Proc Natl Acad Sci USA 2011;108:7541-7546. DOI:10.1073/pnas.1017374108.
• Referans68. O'Day E, Lal A. MicroRNAs and their target gene networks in breast cancer. Breast Cancer Res 2010;12:201. DOI:10.1186/bcr2484.
• Referans69. Walter BA, Gomez-Macias G, Valera VA, Sobel M, Merino MJ. miR-21 expression in pregnancy-associated breast cancer: a possible marker of poor prognosis. J Cancer 2011;2:67-75. DOI:10.7150/jca.2.67.
• Referans70. Moufarrij S, Dandapani M, Arthofer E, Gomez S, Srivastava A, Lopez-Acevedo A, Villagra A, Chiappinelli KB. Epigenetic therapy for ovarian cancer: promise and progress. Clin Epigenetics 2019;11(1):7. DOI:10.1186/s13148-018-0602-0.
• Referans71. Stampoliou A, Arapantoni-Dadioti P, Pavlakis K. Epigenetic mechanisms in endometrial cancer. J Buon 2016;21:301-306. PMID:27273937.
• Referans72. Muller I, Wischnewski F, Pantel K, Schwarzenbach H. Promoter- and cell-specific epigenetic regulation of CD44, Cyclin D2, GLIPR1 and PTEN by methyl-CpG binding proteins and histone modifications. BMC Cancer 2010;10:297. DOI:10.1186/1471-2407-10-29.
• Referans73. Sikand K, Slaibi JE, Singh R, Slane SD, Shukla GC. miR 488* inhibits androgen receptor expression in prostate carcinoma cells. Int J Cancer 2011;129:810-819. DOI:10.1002/ijc.25753.
• Referans74. Majid S, Dar AA, Saini S, Yamamura S, Hirata H, Tanaka Y, Deng G, Dahiya R. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 2010;116:5637-5649. DOI:10.1002/cncr.25488.
• Referans75. Hu M, Xie J, Hou H, Liu M, Wang J. Prognostic Value of DNA Methylation-Driven Genes in Clear Cell Renal Cell Carcinoma: A Study Based on Methylation and Transcriptome Analyses. Dis Markers 2020;2020:8817652. DOI:10.1155/2020/8817652.
• Referans76. Luo Q, Vögeli TA. Methylation-Based Reclassification of Bladder Cancer Based on Immune Cell Genes. Cancers 2020;12:3054. DOI:10.3390/cancers12103054.
• Referans77. Harrison A, Parle-McDermott A. DNA methylation: a timeline of methods and applications. Front Genet 2011;2:74. DOI:10.3389/fgene.2011.00074.
• Referans78. Singer BD. A Practical Guide to the Measurement and Analysis of DNA Methylation. Am J Respir Cell Mol Biol 2019;61(4):417-428. DOI: 10.1165/rcmb.2019-0150TR.