medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC/10.25557/2073-7998.2025.02.3-13medgen-2607Research ArticleНАУЧНЫЙ ОБЗОРREVIEWНарушение метилирования ДНК как фактор задержки развития плодаViolation of DNA methylation as a factor of fetal growth restrictionГавриленкоМ. М.GavrilenkoM. M.

634050, г. Томск, ул. Набережная реки Ушайки, д. 10

10, Naberejnaya Ushaiki, Tomsk, 634050

maria.gavrilenko@medgenetics.ruТрифоноваЕ. А.TrifonovaE. A.

634050, г. Томск, ул. Набережная реки Ушайки, д. 10

10, Naberejnaya Ushaiki, Tomsk, 634050

СтепановВ. А.StepanovV. A.

634050, г. Томск, ул. Набережная реки Ушайки, д. 10

10, Naberejnaya Ushaiki, Tomsk, 634050

Научно-исследовательский институт медицинской генетики Томского национального исследовательского медицинского центра Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical CenterRussian Federation202526032025242313Copyright © Гавриленко М.М., Трифонова Е.А., Степанов В.А., 20252025Гавриленко М.М., Трифонова Е.А., Степанов В.А.Gavrilenko M.M., Trifonova E.A., Stepanov V.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/2607

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.

DNA methylation is a fundamental epigenetic modification mechanism that plays a significant role in gene activity regulation and underlies the development of various diseases. In this article, we have focused on analyzing the genome-wide studies results of DNA methylation in fetal growth restriction (FGR), which reported the identification of differentially methylated regions or genes using high-throughput technologies. Analysis of the included studies has revealed significant alterations in DNA methylation patterns in FGR, affecting 1,022 differentially methylated genes (DMGs), which are overrepresented in the processes of the immune response, the PI3K/AKT/mTOR and MAPK signaling pathways. Among these, only 4% of DMG are replicated between studies. These genes are associated with the signal transduction, cellular morphogenesis, nervous system development and cell adhesion. Additionally, we have identified a cluster of genes that not only exhibited differential methylation in placental tissue but also showed statistically significant changes in gene expression in FGR. These common genes and their products are involved in cell-cell interaction, cell migration, cytoskeleton organization, apoptosis, and nervous system development. The obtained data indicate that certain patterns of DNA methylation associated with the FGR development in the prenatal period may be the basis for increased susceptibility to diseases such as diabetes mellitus, obesity, pathologies of the bronchopulmonary system and immunological dysregulation in later life. The results of our work highlight the important role of a comprehensive analysis of DNA methylation and gene expression for the study of the genetic component underlying FGR.

задержка роста плодаметилированиеэкспрессия геновполногеномные исследованияпатология беременностиfetal growth restrictionmethylationgene expressiongenome-wide studiesobstetric pathologyИсследование выполнено за счет средств государственного задания по теме ФНИ № 122020200083-8.The study was carried out under the state assignment for fundamental research № 122020200083-8.ReferencesSpiers 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.180273.114Spiers 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.180273.114Zaletaev 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.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.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/EBC20190031Law 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/EBC20190031Koukoura 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.2012.763Koukoura 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.2012.763Madeleneau 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.2015.40Madeleneau 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.2015.40Ding 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.2017.04.020Ding 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.2017.04.020Chabrun 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.2019.01292Chabrun 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.2019.01292Lee 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: 10.1080/19768354.2021.1925741Lee 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: 10.1080/19768354.2021.1925741Roifman 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-xRoifman 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-xShi 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.202300742RShi 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.202300742RDing 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.13077Ding 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.13077Karar J., Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Frontiers in molecular neuroscience. 2011;4:51. DOI: 10.3389/fnmol.2011.00051Karar J., Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Frontiers in molecular neuroscience. 2011;4:51. DOI: 10.3389/fnmol.2011.00051Yoshimura 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.46.16Yoshimura 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.46.16Hohn 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: 10.1159/000066965Hohn 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: 10.1159/000066965Lokk 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-r54Lokk 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-r54Miller 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.2023.1125967Miller 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.2023.1125967Sood 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.0508035103Sood 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.0508035103Suryawanshi 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.aau4788Suryawanshi 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.aau4788Lo 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.4835Lo 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.4835Cross 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.xCross 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.xNalivaeva 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.2018.00825Nalivaeva 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.2018.00825Løhaugen 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.2013.01.060Løhaugen 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.2013.01.060Belot 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.12387Belot 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.12387Lundholm 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.xLundholm 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.xWang 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.00042.2020Wang 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.00042.2020Sehgal 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.2022.09.002Sehgal 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.2022.09.002Gantenbein 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.2022.1041718Gantenbein 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.2022.1041718Hales C.N., Barker D.J. The thrifty phenotype hypothesis: Type 2 diabetes. British medical bulletin. 2011;60(1):5-20. DOI: 10.1093/bmb/60.1.5Hales C.N., Barker D.J. The thrifty phenotype hypothesis: Type 2 diabetes. British medical bulletin. 2011;60(1):5-20. DOI: 10.1093/bmb/60.1.5Yzydorczyk 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/S2040174417000265Yzydorczyk 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/S2040174417000265Armengaud 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.2020.10.005Armengaud 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.2020.10.005Zhu 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/bqad195Zhu 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/bqad195Liu S., Zhu N., Chen H. Expression patterns of human DAB2IP protein in fetal tissues. Biotechnic & Histochemistry. 2012;87(5):350–359. DOI: 10.3109/10520295.2012.664658Liu S., Zhu N., Chen H. Expression patterns of human DAB2IP protein in fetal tissues. Biotechnic & Histochemistry. 2012;87(5):350–359. DOI: 10.3109/10520295.2012.664658Shan 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: 10.3109/14767058.2014.1001974Shan 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: 10.3109/14767058.2014.1001974Zhang 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/s11596-023-2738-1Zhang 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/s11596-023-2738-1Zeng 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: 10.1080/14767058.2023.2207708Zeng 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: 10.1080/14767058.2023.2207708Saad 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-zSaad 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-zGalindo-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.2020.155362Galindo-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.2020.155362Marginean 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.0000000000005551Marginean 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.0000000000005551Su 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).0024Su 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).0024Wan 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.0071202Wan 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.0071202Fekete 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.2005.08.021Fekete 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.2005.08.021Kaartokallio 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.2024.109047Kaartokallio 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.2024.109047Zhou 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/JCI6696Zhou 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/JCI6696Eude-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-S11Eude-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-S11Metsalu 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: 10.4161/15592294.2014.970052Metsalu 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: 10.4161/15592294.2014.970052Xu 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.2013.1499Xu 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.2013.1499Li 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.2022.114792Li 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.2022.114792Ha 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.63559Ha 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.63559Camerota 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/dev0001709Camerota 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/dev0001709Mathews 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: 10.1177/1535370220980398Mathews 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: 10.1177/1535370220980398Schulze 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-zSchulze 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-zYang 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/s13148-022-01412-6Yang 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/s13148-022-01412-6Wang 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.2022.875180Wang 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.2022.875180Williams 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/s00125-016-3983-7Williams 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/s00125-016-3983-7Gavrilenko 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.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.Ehrlich M. DNA hypermethylation in disease: mechanisms and clinical relevance. Epigenetics. 2019;14(12):1141–1163. DOI: 10.1080/15592294.2019.1638701Ehrlich M. DNA hypermethylation in disease: mechanisms and clinical relevance. Epigenetics. 2019;14(12):1141–1163. DOI: 10.1080/15592294.2019.1638701Botto 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.1994.2777Botto 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.1994.2777Rauluseviciute 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/s12920-020-0657-6Rauluseviciute 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/s12920-020-0657-6Zhao 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/ncb2303Zhao 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/ncb2303Albers 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/s41598-019-39426-5Albers 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

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