Epigenetic modulation in medicine: Regulation of gene expression in the context of pathogenesis and therapy

Epigenetics plays a critical role relative to other branches of genetics, as it makes it possible to regulate gene expression without changing the nucleotide sequence of DNA molecules. This process allows cells to respond to external signals and adapt to  changes in  the  environment while keeping their genetic information intact. The  main mechanisms of  epigenetic regulation include DNA methylation, posttranslational modifications of  histones, chromatin remodeling and  regulation through non-coding RNAs. These processes play a key role in fundamental biological processes such as cellular differentiation, organismal development, and adaptation to environmental conditions.

Disturbances in epigenetic mechanisms can lead to various pathologies, including cancer, neurological and  autoimmune diseases. Understanding the  mechanisms of  epigenetic regulation opens new avenues for  the  development of  targeted therapies that can correct abnormal epigenetic profiles without changing the DNA structure itself.

In  recent years, the  development and  application of  innovative technologies, such  as  the  CRISPR/Cas9 genome editing system, have significantly expanded the ability to study epigenetic mechanisms and their relationship with diseases. These technologies allow not only a deeper understanding of epigenetic changes, but also the development of new therapeutic approaches, especially in the field of oncology. Research in  epigenetics is  also focusing on  the  interaction between epigenetic changes and the immune system, which opens new perspectives for the development of immunotherapies. The search for new markers of epigenetic disorders and therapeutic agents may lead to the development of individualized treatments that take into account the unique epigenetic profile of each patient.

The role of epigenetic modifications in the development of diseases and the creation of new therapeutic strategies cannot be overestimated. Recent research in this area is revealing the potential of epigenetic approaches to treat a wide range of diseases, ushering in a new era in medicine where understanding and correcting epigenetic changes will be the key to effective treatment.

1. van Speybroeck L. From epigenes to epigenetics: The case of C.H. Waddington. Ann N Y Acad Sci. 2002; 981: 61-81.

2. Li Y. Modern epigenetics methods in biological research. Methods. 2021; 187: 104-113. doi: 10.1016/j.ymeth.2020.06.022

3. Ziganshin AM, Mulyukov AR, Omarov MA, Mudrov VA, Khalitova RSh. Prospects for using CRISPR/Cas9 system in the treatment of human viral diseases. Acta biomedica scientifica. 2023; 8(1): 40-50. (In Russ.). doi: 10.29413/ABS.2023-8.1.5

4. Sharipov RA, Omarov MA, Mulyukov AR, Dybova AI, Vyaseleva ET, Kayumova NB, et al. Benefits of using the CRISPR/ Cas9 system in the modification of genetic disorders. Molecular Genetics, Microbiology and Virology. 2023; 41(3): 3-8. (In Russ.). doi: 10.17116/molgen2023410313

5. Ansari I, Chaturvedi A, Chitkara D, Singh S. CRISPR/Cas mediated epigenome editing for cancer therapy. Semin Cancer Biol. 2022; 83: 570-583. doi: 10.1016/j.semcancer.2020.12.018

6. Yao S, He Z, Chen C. CRISPR/Cas9-mediated genome editing of epigenetic factors for cancer therapy. Human Gene Ther. 2015; 26(7): 463-471. doi: 10.1089/hum.2015.067

7. Maksimenko LV. Epigenetics as an evidence base of the impact of lifestyle on health and disease. Russian Journal of Preventive Medicine. 2019; 22(2): 115-120. (In Russ.). doi: 10.17116/profmed201922021115

8. Zanyatkin IA, Titova AG, Bayov AV. Modern methods for analysis of changes to epigenetic landscape caused by exposure to environmental pollutants. Extreme Medicine. 2021; 23(1): 39-47. (In Russ.). doi: 10.47183/mes.2021.003

9. Refn MR, Andersen MM, Kampmann ML, Tfelt-Hansen J, Sørensen E, Larsen MH, et al. Longitudinal changes and variation in human DNA methylation analysed with the Illumina MethylationEPIC BeadChip assay and their implications on forensic age prediction. Sci Rep. 2023; 13(1): 21658. doi: 10.1038/s41598-023-49064-7

10. Kaplun DS, Kaluzhny DN, Prokhortchouk EB, Zhenilo SV. DNA methylation: Genomewide distribution, regulatory mechanism and therapy target. Acta Naturae. 2022; 14(4): 4-19. (In Russ.). doi: 10.32607/actanaturae.11822

11. Chen X, Xu X, Shen X, Li H, Zhu C, Chen R, et al. Genomewide investigation of DNA methylation dynamics reveals a critical role of DNA demethylation during the early somatic embryogenesis of Dimocarpus longan Lour. Tree Physiol. 2020; 40(12): 1807- 1826. doi: 10.1093/treephys/tpaa097

12. Zhu L, Li X, Yuan Y, Dong C, Yang M. APC promoter methylation in gastrointestinal cancer. Front Oncol. 2021; 11: 653222. doi: 10.3389/fonc.2021.653222

13. Seo EH, Kim HJ, Kim JH, Lim B, Park JL, Kim SY, et al. ONECUT2 upregulation is associated with CpG hypomethylation at promoter-proximal DNA in gastric cancer and triggers ACSL5. Int J Cancer. 2020; 146(12): 3354-3368. doi: 10.1002/ijc.32946

14. Nuzhnyi EP, Abramycheva NYu, Nikolaeva NS, Ershova MV, Klyushnikov SA, Illarioshkin SN, et al. Epigenetic regulation of clinical manifestations of Friedreich’s disease. S.S. Korsakov Journal of Neurology and Psychiatry. 2020; 120(1): 20-26. (In Russ.). doi: 10.17116/jnevro202012001120

15. Hammond CM, Strømme CB, Huang H, Patel DJ, Groth A. Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol. 2017; 18(3): 141-158. doi: 10.1038/nrm.2016.159

16. Martire S, Gogate AA, Whitmill A, Tafessu A, Nguyen J, Teng YC, et al. Phosphorylation of histone H3.3 at serine 31 promotes p300 activity and enhancer acetylation. Nat Gen. 2019; 51(6): 941-946. doi: 10.1038/s41588-019-0428-5

17. Yang Z, Xu F, Teschendorff AE, Zhao Y, Yao L, Li J, et al. Insights into the role of long non-coding RNAs in DNA methylation mediated transcriptional regulation. Front Biosci. 2022; 9: 1067406. doi: 10.3389/fmolb.2022.1067406

18. Zhang L, Chai R, Tai Z, Miao F, Shi X, Chen Z, et al. Noval advance of histone modification in inflammatory skin diseases and related treatment methods. Front Immunol. 2024; 14: 1286776. doi: 10.3389/fimmu.2023.1286776

19. Karpenko DV, Petinati NA, Drize NJ, Bigildeev AE. The role of epigenetic modifications of DNA and histones in the treatment of oncohematological diseases. Russian Journal of Hematology and Transfusiology. 2021; 66(2): 263-279. (In Russ.). doi: 10.35754/0234-5730-2021-66-2-263-279

20. Bushueva OYu, Barysheva EM, Markov AV, Koroleva YuA, Churkin EO, Nazarenko MS, et al. Molecular and epigenetic mechanisms of the involvement of redox-homeostasis genes in the development of various cardiovascular diseases. Medical Genetics. 2020; 19(5): 66-68. (In Russ.). doi: 10.25557/2073-7998.2020.05.66-68

21. Garcia-Martinez L, Zhang Y, Nakata Y, Chan HL, Morey L. Epigenetic mechanisms in breast cancer therapy and resistance. Nat Commun. 2021; 12(1): 1786. doi: 10.1038/s41467-021-22024-3

22. Yin J, Gu T, Chaudhry N, Davidson NE, Huang Y. Epigenetic modulation of antitumor immunity and immunotherapy response in breast cancer: Biological mechanisms and clinical implications. Front Immunol. 2024; 14: 1325615. doi: 10.3389/fimmu.2023.1325615

23. Mathur R, Jha NK, Saini G, Jha SK, Shukla SP, Filipejová Z, et al. Epigenetic factors in breast cancer therapy. Front Gen. 2022; 13: 886487. doi: 10.3389/fgene.2022.886487

24. Wu J, Chai H, Shan H, Pan C, Xu X, Dong W, et al. Histone methyltransferase SETD1A induces epithelial-mesenchymal transition to promote invasion and metastasis through epigenetic reprogramming of snail in gastric cancer. Front Cell Dev Biol. 2021; 9: 657888. doi: 10.3389/fcell.2021.657888

25. Cheng JT, Wang L, Wang H, Tang FR, Cai WQ, Sethi G, et al. Insights into biological role of LncRNAs in epithelial-mesenchymal transition. Cells. 2019; 8(10): 1178. doi: 10.3390/cells8101178

26. Prieto-García E, Díaz-García CV, García-Ruiz I, AgullóOrtuño MT. Epithelial-to-mesenchymal transition in tumor progression. Med Oncol. 2017; 34(7): 122. doi: 10.1007/s12032-017-0980-8

27. Uddin MS, Mamun AA, Alghamdi BS, Tewari D, Jeandet P, Sarwar MS, et al. Epigenetics of glioblastoma multiforme: From molecular mechanisms to therapeutic approaches. Sem Cancer Biol. 2022; 83: 100-120. doi: 10.1016/j.semcancer.2020.12.015

28. Rönn T, Ofori JK, Perfilyev A, Hamilton A, Pircs K, Eichelmann F, et al. Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes. Nat Commun. 2023; 14(1): 8040. doi: 10.1038/s41467-023-43719-9

29. Loh M, Zhou L, Ng HK, Chambers JC. Epigenetic disturbances in obesity and diabetes: Epidemiological and functional insights. Mol Metab. 2019; 27(Suppl): S33-S41. doi: 10.1016/j.molmet.2019.06.011

30. Wu X, Xu M, Geng M, Chen S, Little PJ, Xu S, et al. Targeting protein modifications in metabolic diseases: Molecular mechanisms and targeted therapies. Signal Transduct Target Ther. 2023; 8(1): 220. doi: 10.1038/s41392-023-01439-y

31. Gomazkov OA. Signaling molecules in the brain and epigenetic factors in neurodegenerative and mental disorders. S.S. Korsakov Journal of Neurology and Psychiatry. 2015; 115(10): 102-110. (In Russ.). doi: 10.17116/jnevro2015115101102-110

32. Emelyanov Ak, Lavrinova AO, Melnikova NV, Dmitriev AA, Miliukhina IV, Timofeeva AA, et al. Epigenetic regulation of SNCA gene expression in Parkinson’s disease. Medical Genetics. 2020; 19(4): 96-98. (In Russ.). doi: 10.25557/2073-7998.2020.04.96-98

33. Smith AR, Smith RG, Pishva E, Hannon E, Roubroeks JAY, Burrage J, et al. Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer’s disease. Clin Epigenetics. 2019; 11(1): 52. doi: 10.1186/s13148-019-0636-y

34. Yakovenko EV, Fedotova EY, Illarioshkin SN. DNA methylation in Parkinson disease. Annals of Clinical and Experimental Neurology. 2020; 14(4): 75-81. (In Russ.). doi: 10.25692/ACEN.2020.4.10

35. Song H, Chen J, Huang J, Sun P, Liu Y, Xu L, et al. Epigenetic modification in Parkinson’s disease. Front Cell Dev Biol. 2023; 11: 1123621. doi: 10.3389/fcell.2023.1123621

36. McMillan KJ, Murray TK, Bengoa-Vergniory N, CorderoLlana O, Cooper J, Buckley A, et al. Loss of MicroRNA-7 regulation leads to α-synuclein accumulation and dopaminergic neuronal loss in vivo. Mol Ther. 2017; 25(10): 2404-2414. doi: 10.1016/j.ymthe.2017.08.017

37. Moodie FM, Marwick JA, Anderson CS, Szulakowski P, Biswas SK, Bauter MR, et al. Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells. FASEB J. 2004; 18(15): 1897-1899. doi: 10.1096/fj.04-1506fje

38. Dailah HG. Therapeutic potential of small molecules targeting oxidative stress in the treatment of chronic obstructive pulmonary disease (COPD): A comprehensive review. Molecules. 2022; 27(17): 5542. doi: 10.3390/molecules27175542

39. Chaulin AM, Duplyakov DV. Comorbidity in chronic obstructive pulmonary disease and cardiovascular disease. Cardiovascular Therapy and Prevention. 2021; 20(3): 2539. (In Russ.). doi: 10.15829/1728-8800-2021-2539

40. Kato R, Mizuno S, Kadowaki M, Shiozaki K, Akai M, Nakagawa K, et al. Sirt1 expression is associated with CD31 expression in blood cells from patients with chronic obstructive pulmonary disease. Respir Res. 2016; 17(1): 139. doi: 10.1186/s12931-016-0452-2

41. Günes Günsel G, Conlon TM, Jeridi A, Kim R, Ertüz Z, Lang NJ, et al. The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD. Nat Commun. 2022; 13(1): 1303. doi: 10.1038/s41467-022-28809-4

42. Mongelli A, Atlante S, Bachetti T, Martelli F, Farsetti A, Gaetano C. Epigenetic signaling and RNA regulation in cardiovascular diseases. Int J Mol Sci. 2020; 21(2): 509. doi: 10.3390/ijms21020509

43. Liu Y, Peng W, Qu K, Lin X, Zeng Z, Chen J, et al. TET2: A novel epigenetic regulator and potential intervention target for atherosclerosis. DNA Cell Biol. 2018; 37(6): 517-523. doi: 10.1089/dna.2017.4118

44. Chapski DJ, Cabaj M, Morselli M, Mason RJ, Soehalim E, Ren S, et al. Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart. J Mol Cell Cardiol. 2021; 160: 73-86. doi: 10.1016/j.yjmcc.2021.07.002

45. Markus HS, Mäkelä KM, Bevan S, Raitoharju E, Oksala N, Bis JC, et al. Evidence HDAC9 genetic variant associated with ischemic stroke increases risk via promoting carotid atherosclerosis. Stroke. 2013; 44(5): 1220-1225. doi: 10.1161/STROKEAHA.111.000217

46. Pappalardi MB, Keenan K, Cockerill M, Kellner WA, Stowell A, Sherk C, et al. Discovery of a first-in-class reversible DNMT1- selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nat Rev Cancer. 2021; 2(10): 1002-1017.

47. Merkerova MD, Klema J, Kundrat D, Szikszai K, Krejcik Z, Hrustincova A, et al. Noncoding RNAs and their response predictive value in azacitidine-treated patients with myelodysplastic syndrome and acute myeloid leukemia with myelodysplasiarelated changes. Cancer Genomics Proteomics. 2022; 19(2): 205-228. doi: 10.21873/cgp.20315

48. Jenke R, Reßing N, Hansen FK, Aigner A, Büch T. Anticancer therapy with HDAC inhibitors: Mechanism-based combination strategies and future perspectives. Cancers (Basel). 2021; 13(4): 634. doi: 10.3390/cancers13040634

49. Wu Q, Schapira M, Arrowsmith CH, Barsyte-Lovejoy D. Protein arginine methylation: From enigmatic functions to therapeutic targeting. Nat Rev Drug Discov. 2021; 20(7): 509-530. doi: 10.1038/s41573-021-00159-8

50. Mersaoui SY, Yu Z, Coulombe Y, Karam M, Busatto FF, Masson JY, et al. Arginine methylation of the DDX5 helicase RGG/RG motif by PRMT5 regulates resolution of RNA: DNA hybrids. EMBO J. 2019; 38(15): e100986. doi: 10.15252/embj.2018100986

51. Fedoriw A, Rajapurkar SR, O’Brien S, Gerhart SV, Mitchell LH, Adams ND, et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell. 2019; 36(1): 100-114.e25. doi: 10.1016/j.ccell.2019.05.014

52. Spivack SD. Inactivation of endogenous genes in cancer cells using targeted promoter DNA methylation via CRISPR-DNMT3a fusion protein. Cancer Res. 2017; 77(13). doi: 10.1158/1538-7445.AM2017-5380

53. Zhou S, Dong J, Deng L, Wang G, Yang M, Wang Y, et al. Endonuclease-assisted PAM-free recombinase polymerase amplification coupling with CRISPR/Cas12a (E-PfRPA/Cas) for sensitive detection of DNA methylation. ACS Sensors. 2022; 7(10): 3032-3040. doi: 10.1021/acssensors.2c01330

54. Hilton IB, D’Ippolito AM, Vockley CM, Thakore PI, Crawford GE, Reddy TE, et al. Epigenome editing by a CRISPRCas9-based acetyltransferase activates genes from promoters and enhancers. Nat Biotechnol. 2015; 33(5): 510-517. doi: 10.1038/nbt.3199

55. Chapman B, Han JH, Lee HJ, Ruud I, Kim TH. Targeted modulation of chicken genes in vitro using CRISPRa and CRISPRi toolkit. Genes (Basel). 2023; 14(4): 906. doi: 10.3390/genes14040906

56. Baron U, Floess S, Wieczorek G, Baumann K, Grützkau A, Dong J, et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur J Immunol. 2007; 37(9): 2378-2389. doi: 10.1002/eji.200737594

57. Vad-Nielsen J, Staunstrup NH, Kjeldsen ML, Dybdal N, Flandin G, De Stradis C, et al. Genome-wide epigenetic and mRNAexpression profiling followed by CRISPR/Cas9-mediated gene- disruptions corroborate the MIR141/MIR200C-ZEB1/ZEB2-FGFR1 axis in acquired EMT-associated EGFR TKI-resistance in NSCLC cells. Transl Lung Cancer Res. 2023; 12(1): 42-65. doi: 10.21037/tlcr-22-507

58. Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of inflammatory cytokines within the breast tumor microenvironment. Int J Mol Sci. 2023; 24: 4002. doi: 10.3390/ijms24044002

59. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: Signaling pathways and targeted intervention. Signal Transduct and Targeted Therapy. 2021; 6(1): 263. doi: 10.1038/s41392-021-00658-5

60. Jones SA, Jenkins BJ. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol. 2018; 18(12): 773-789. doi: 10.1038/s41577-018-0066-7

61. Ivanenko KA, Prassolov VS, Khabusheva ER. Transcription factor Sp1 in the expression of genes encoding components of MAPK, JAK/STAT, and PI3K/Akt signaling pathways. Mol Biol. 2022; 56(5): 832-847. (In Russ.). doi: 10.31857/S0026898422050081

62. O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. The JAK-STAT pathway: Impact on human disease and therapeutic intervention. Ann Rev Med. 2015; 66: 311- 328. doi: 10.1146/annurev-med-051113-024537