Нарушение метилирования ДНК как фактор задержки развития плода

Метилирование ДНК является фундаментальным механизмом эпигенетической модификации, который играет значимую роль в регуляции активности генов и лежит в основе развития ряда заболеваний. В настоящей статье мы сфокусировались на анализе результатов полногеномных исследований метилирования при задержке роста плода (ЗРП), в которых сообщалось об идентификации дифференциально метилированных областей или генов с использованием высокопроизводительных технологий. Анализ результатов включенных работ показал, что при ЗРП наблюдается значительное изменение паттернов метилирования ДНК, затрагивающее 1022 дифференциально метилированных гена (ДМГ), которые сверхпредставлены в процессах иммунного ответа, сигнальных путей PI3K/AKT/mTOR и MAPK. Из них только 4% ДМГ, связанных с процессами трансдукции сигнала, клеточного морфогенеза, формировании нервной системы и межклеточной адгезии, реплицируются между исследованиями. Кроме того, нами выявлен кластер генов, для которых наряду с дифференциальным метилированием в плацентарной ткани обнаружено также статистически значимое изменение экспрессии генов при ЗРП. Эти общие гены и их продукты принимают участие в процессах межклеточного взаимодействия, миграции клеток, организации цитоскелета, апоптоза и развития нервной системы. Полученные данные свидетельствуют о том, что определенные паттерны метилирования ДНК, ассоциированные с развитием ЗРП во внутриутробном периоде, могут являться основой для повышенной восприимчивости к таким заболеваниям как сахарный диабет, ожирение, патология бронхолегочной системы и иммунологическая дизрегуляция в дальнейшей жизни. Результаты нашей работы указывают на важную роль комплексного полногеномного анализа метилирования ДНК и экспрессии генов в изучении генетической компоненты, лежащей в основе ЗРП.

1. Spiers H., Hannon E., Schalkwyk L.C., et al. Methylomic trajectories across human fetal brain development. Genome research. 2015;25(3):338–352. DOI: 10.1101/gr.180273.114

2. Zaletaev D.V., Nemtsova M.V., Strelnikov V.V., et al. Diagnostics of epigenetic alterations in hereditary and oncological disorders. Molecular biology. 2004;38(2): 174-182.

3. Law P.P., Holland M.L. DNA methylation at the crossroads of gene and environment interactions. Essays in biochemistry. 2019;63(6):717–726. DOI: 10.1042/EBC20190031

4. Koukoura O., Sifakis S., Spandidos D.A. DNA methylation in the human placenta and fetal growth. Molecular medicine reports. 2012;5(4):883–889. DOI: 10.3892/mmr.2012.763

5. Madeleneau D., Buffat C., Mondon F., et al. Transcriptomic analysis of human placenta in intrauterine growth restriction. Pediatric Research. 2015;77(6):799–807. DOI: 10.1038/pr.2015.40

6. Ding Y., Cui H.. Integrated analysis of genome-wide DNA methylation and gene expression data provide a regulatory network in intrauterine growth restriction. Life Sciences. 2017;179:60–65. DOI: 10.1016/j.lfs.2017.04.020

7. Chabrun F., Huetz N., Dieu X., et al. Data-mining approach on transcriptomics and methylomics placental analysis highlights genes in fetal growth restriction. Frontiers in Genetics. 2020;10:1292. DOI: 10.3389/fgene.2019.01292

8. Lee S., Kim Y.N., Im D., et al. DNA Methylation and gene expression patterns are widely altered in fetal growth restriction and associated with FGR development. Animal Cells and Systems. 2021;25(3):128–135. DOI: 10.1080/19768354.2021.1925741

9. Roifman M., Choufani S., Turinsky A.L., et al. Genome-wide placental DNA methylation analysis of severely growth-discordant monochorionic twins reveals novel epigenetic targets for intrauterine growth restriction. Clinical epigenetics. 2016;8(1):1–13. DOI: 10.1186/s13148-016-0238-x

10. Shi D., Zhou X., Cai L., et al. Placental DNA methylation analysis of selective fetal growth restriction in monochorionic twins reveals aberrant methylated CYP11A1 gene for fetal growth restriction. The FASEB Journal. 2023;37(10): e23207. DOI: 10.1096/fj.202300742R

11. Ding J., Maxwell A., Adzibolosu N., et al. Mechanisms of immune regulation by the placenta: Role of type I interferon and interferonstimulated genes signaling during pregnancy. Immunological reviews. 2022;308(1):9–24. DOI: 10.1111/imr.13077

12. Karar J., Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Frontiers in molecular neuroscience. 2011;4:51. DOI: 10.3389/fnmol.2011.00051

13. Yoshimura Y. Integrins: expression, modulation, and signaling in fertilization, embryogenesis and implantation. The Keio journal of medicine. 1997;46(1):16–24. DOI: 10.2302/kjm.46.16

14. Hohn H.P., Denker H.W. Experimental modulation of cell-cell adhesion, invasiveness and differentiation in trophoblast cells. Cells Tissues Organs. 2002;172(3):218–236. DOI: 10.1159/000066965

15. Lokk K., Modhukur V., Rajashekar B., et al. DNA methylome profiling of human tissues identifies global and tissue-specific methylation patterns. Genome biology. 2014;1594):1–14. DOI: 10.1186/gb-2014-15-4-r54

16. Miller R.H., Pollard C.A., Brogaard K.R., et al. Tissue-specific DNA methylation variability and its potential clinical value. Frontiers in Genetics. 2023;14:1125967. DOI: 10.3389/fgene.2023.1125967

17. Sood R., Zehnder J.L., Druzin M.L., et al. Gene expression patterns in human placenta. Proceedings of the National Academy of Sciences. 2006;103(14):5478–5483. DOI: 10.1073/pnas.0508035103

18. Suryawanshi H., Morozov P., Straus A., et al. A single-cell survey of the human first-trimester placenta and decidua. Science advances. 2018;4(10):eaau4788. DOI: 10.1126/sciadv.aau4788

19. Lo H.F., Tsai C.Y., Chen C.P., et al. Association of dysfunctional synapse defective 1 (SYDE1) with restricted fetal growth–SYDE1 regulates placental cell migration and invasion. The Journal of Pathology. 2017;241(3):324–336. DOI: 10.1002/path.4835

20. Cross J.C., Nakano H., Natale D.R., et al. Branching morphogenesis during development of placental villi. Differentiation. 2006;74(7):393–401. DOI: 10.1111/j.1432-0436.2006.00103.x

21. Nalivaeva N.N., Turner A.J., Zhuravin I.A. Role of prenatal hypoxia in brain development, cognitive functions, and neurodegeneration. Frontiers in neuroscience. 2018;12:825. DOI: 10.3389/fnins.2018.00825

22. Løhaugen G.C., Østgård H.F., Andreassen S., et al. Small for gestational age and intrauterine growth restriction decreases cognitive function in young adults. The Journal of pediatrics. 2013;163(2):447– 453. DOI: 10.1016/j.jpeds.2013.01.060

23. Belot M.P., Nadéri K., Mille C., et al. Role of DNA methylation at the placental RTL1 gene locus in type 1 diabetes. Pediatric Diabetes. 2017;18(3):178–187. DOI: 10.1111/pedi.12387

24. Lundholm C., Örtqvist A.K., Lichtenstein P., et al. Impaired fetal growth decreases the risk of childhood atopic eczema: a Swedish twin study. Clinical & Experimental Allergy. 2010;40(7):1044–1053. DOI: 10.1111/j.1365-2222.2010.03519.x

25. Wang K.C., James A.L., Noble P.B. Fetal growth restriction and asthma: is the damage done?. Physiology. 2021;36(4):256–266. DOI: 10.1152/physiol.00042.2020

26. Sehgal A., Dassios T., Nold M.F., et al. Fetal growth restriction and neonatal-pediatric lung diseases: Vascular mechanistic links and therapeutic directions. Paediatric respiratory reviews. 2022;44:19– 30. DOI: 10.1016/j.prrv.2022.09.002

27. Gantenbein K.V., Kanaka-Gantenbein C. Highlighting the trajectory from intrauterine growth restriction to future obesity. Frontiers in endocrinology. 2022;13:1041718. DOI: 10.3389/fendo.2022.1041718

28. Hales C.N., Barker D.J. The thrifty phenotype hypothesis: Type 2 diabetes. British medical bulletin. 2011;60(1):5-20. DOI: 10.1093/bmb/60.1.5

29. Yzydorczyk C., Armengaud J.B., Peyter A.C., et al. Endothelial dysfunction in individuals born after fetal growth restriction: cardiovascular and renal consequences and preventive approaches. Journal of developmental origins of health and disease. 2017;8(4):448–464. DOI: 10.1017/S2040174417000265

30. Armengaud J.B., Yzydorczyk C., Siddeek B., et al. Intrauterine growth restriction: Clinical consequences on health and disease at adulthood. Reproductive Toxicology. 2021;99:168–176. DOI: 10.1016/j.reprotox.2020.10.005

31. Zhu Y.N., Pan F., Gan X.W., et al. The Role of DNMT1 and C/ EBPα in the Regulation of CYP11A1 Expression During Syncytialization of Human Placental Trophoblasts. Endocrinology. 2024;165(2):bqad195. DOI: 10.1210/endocr/bqad195

32. Liu S., Zhu N., Chen H. Expression patterns of human DAB2IP protein in fetal tissues. Biotechnic & Histochemistry. 2012;87(5):350–359. DOI: 10.3109/10520295.2012.664658

33. Shan N., Xiao X., Chen Y., et al. Expression of DAB2IP in human trophoblast and its role in trophoblast invasion. The Journal of Maternal-Fetal & Neonatal Medicine. 2016;29(3):393–399. DOI: 10.3109/14767058.2014.1001974

34. Zhang J.Y., Jiang Y., Wei L.J., et al. LncRNA HCG27 promotes glucose uptake ability of HUVECs by MiR-378a-3p/MAPK1 pathway. Current Medical Science. 2023;43(4):784-793. DOI: 10.1007/s11596-023-2738-1

35. Zeng S., Wu Y., Zhou M., et al. Association between genetic polymorphisms of leptin receptor and preeclampsia in Chinesewomen. The Journal of Maternal-Fetal & Neonatal Medicine. 2023;36(1):2207708. DOI: 10.1080/14767058.2023.2207708

36. Saad A., Adam I., Elzaki S.E.G., et al. Leptin receptor gene polymorphisms c. 668A> G and c. 1968G> C in Sudanese women with preeclampsia: a case-control study. BMC Medical Genetics. 2020;21:1–8. DOI: 10.1186/s12881-020-01104-z

37. Galindo-Cáceres M.A., Parra-Unda R., Murillo-Llanes J., et al. Association of leptin receptor expression in placenta and peripheral blood mononuclear cell with maternal weight in birth outcomes. Cytokine. 2021;138:155362. DOI: 10.1016/j.cyto.2020.155362

38. Marginean C., Marginean C.O., Iancu M., et al. The FTO rs9939609 and LEPR rs1137101 mothers–newborns gene polymorphisms and maternal fat mass index effects on anthropometric characteristics in newborns: a cross-sectional study on mothers–newborns gene polymorphisms—The FTO-LEPR Study (STROBE-compliant article). Medicine. 2016; 95(49):e5551. DOI: 10.1097/MD.0000000000005551

39. Su C., Yu T., Zhao R., et al. Subclinical thyroid disease and single nucleotide polymorphisms in reproductive-age women in areas of Shanxi Province, China, where iodine exposure is excessive. Asia Pacific Journal of Clinical Nutrition. 2018;27(6): 1366–1373. DOI: 10.6133/apjcn.201811_27(6).0024

40. Wan J.P., Zhao H., Li T., et al. The common variant rs11646213 is associated with preeclampsia in Han Chinese women. PloS one. 2013;8(8):e71202. DOI: 10.1371/journal.pone.0071202

41. Fekete A., Vér Á., Bögi K., et al. Is preeclampsia associated with higher frequency of HSP70 gene polymorphisms? European Journal of Obstetrics & Gynecology and Reproductive Biology. 2006;126(2):197–200. DOI: 10.1016/j.ejogrb.2005.08.021

42. Kaartokallio T., Cervera A., Kyllönen A., et al. Gene expression profiling of pre-eclamptic placentae by RNA sequencing. Scientific reports. 2015;5(1):14107. DOI: 10.1016/j.isci.2024.109047

43. Zhou Y., Gormley M.J., Hunkapiller N.M., et al. Reversal of gene dysregulation in cultured cytotrophoblasts reveals possible causes of preeclampsia. The Journal of clinical investigation. 2013;123(7):2862–2872. DOI: 10.1172/JCI6696

44. Eude-Le Parco I., Dallot E., Breuiller-Fouché M. Protein kinase C and human uterine contractility. BMC Pregnancy and Childbirth. 2007;7:S11. DOI: 10.1186/1471-2393-7-S1-S11

45. Metsalu T., Viltrop T., Tiirats A., et al. Using RNA sequencing for identifying gene imprinting and random monoallelic expression in human placenta. Epigenetics. 2014;9(10):1397-1409. DOI: 10.4161/15592294.2014.970052

46. Xu Y., Li W., Liu X., et al. Analysis of microRNA expression profile by small RNA sequencing in Down syndrome fetuses. International journal of molecular medicine. 2013;32(5):1115-1125. DOI: 10.3892/ijmm.2013.1499

47. Li Y., Sun C., Guo Y., et al. DIP2C polymorphisms are implicated in susceptibility and clinical phenotypes of autism spectrum disorder. Psychiatry Research. 2022;316: 114792. DOI: 10.1016/j.psychres.2022.114792

48. Ha T., Morgan A., Bartos M.N., et al. De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay. American Journal of Medical Genetics Part A. 2024:e63559. DOI: 10.1002/ajmg.a.63559

49. Camerota M., Lester B.M., McGowan E.C., et al. Contributions of prenatal risk factors and neonatal epigenetics to cognitive outcome in children born very preterm. Developmental Psychology. 2024;60(9):1606–1619. DOI: 10.1037/dev0001709

50. Mathews E., Dewees K., Diaz D., Favero C. White matter abnormalities in fetal alcohol spectrum disorders: focus on axon growth and guidance. Experimental Biology and Medicine. 2021;246(7):812–821. DOI: 10.1177/1535370220980398

51. Schulze K.V., Bhatt A., Azamian M.S., et al. Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. Genetics in Medicine. 2019;21(11):2453–2461. DOI: 10.1038/s41436-019-0516-z

52. Yang M.N., Huang R., Zheng T., et al. Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors. Clinical Epigenetics. 2022;14(1):192. DOI: 10.1186/s13148-022-01412-6

53. Wang W.J., Huang R., Zheng T., et al. Genome-wide placental gene methylations in gestational diabetes mellitus, fetal growth and metabolic health biomarkers in cord blood. Frontiers in endocrinology. 2022;13:875180. DOI: 10.3389/fendo.2022.875180

54. Williams L., Seki Y., Delahaye F., et al. DNA hypermethylation of CD3+ T cells from cord blood of infants exposed to intrauterine growth restriction. Diabetologia. 2016;59:1714–1723. DOI: 10.1007/s00125-016-3983-7

55. Gavrilenko M.M., Trifonova E.A., Stepanov V.A. Genome-Wide Analysis in the Study of the Fetal Growth Restriction Pathogenetics. Russian Journal of Genetics. 2024;60(8):1001–1013.

56. Ehrlich M. DNA hypermethylation in disease: mechanisms and clinical relevance. Epigenetics. 2019;14(12):1141–1163. DOI: 10.1080/15592294.2019.1638701

57. Botto F., Seree E., Elkhyari S., et al. Hypomethylation and hypoexpression of human CYP2E1 gene in lung tumors. Biochemical and biophysical research communications. 1994;205(2):1086–1092. DOI: 10.1006/bbrc.1994.2777

58. Rauluseviciute I., Drabløs F., Rye M.B. DNA hypermethylation associated with upregulated gene expression in prostate cancer demonstrates the diversity of epigenetic regulation. BMC medical genomics. 2020;13:1–15. DOI: 10.1186/s12920-020-0657-6

59. Zhao B., Tumaneng K., Guan K.L. The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature cell biology. 2011;13(8):877–883. DOI: 10.1038/ncb2303

60. Albers R.E., Kaufman M.R., Natale B.V., et al. Trophoblast-specific expression of Hif-1α results in preeclampsia-like symptoms and fetal growth restriction. Scientific Reports. 2019;9(1):2742. DOI: 10.1038/s41598-019-39426-5