Мобильные элементы как ключевые регуляторы развития плаценты

   Мобильные элементы (transposable elements, TE), составляющие свыше трети человеческого генома, играют ключевую роль в его эволюции, выступая важным источником регуляторных последовательностей. В норме их активность жестко контролируется механизмами метилирования ДНК, однако эффективность такого подавления существенно различается между тканями. Плацента, отличающаяся глобальным гипометилированием, представляет собой уникальную среду, где ретровирусы и ретротранспозоны, обычно молчащие в соматических клетках, получают возможность активации. Этот особый эпигенетический ландшафт плаценты позволяет транспозонам участвовать в регуляции геномной активности, оказывая влияние на процессы, протекающие от раннего эмбриогенеза до постнатального развития. Гипометилирование ДНК в плаценте не только способствует мобилизации TE, но и открывает возможность использования их компонентов в качестве самостоятельных генов и регуляторных элементов – промоторов, энхансеров и других функциональных модулей. Эти элементы вовлечены в ключевые аспекты плацентарного развития, включая формирование синцитиотрофобласта, инвазию вневорсинчатого трофобласта, ремоделирование спиральных артерий и децидуализацию эндометрия. Важно отметить, что TE могут служить источниками альтернативных промоторов для соседних генов, а древние транспозоны млекопитающих содержат множественные сайты связывания транскрипционных факторов, обеспечивая скоординированную регуляцию генов, объединенных общей функцией. Несмотря на растущий интерес к роли мобильных элементов в развитии и функционировании плаценты, многие вопросы остаются без ответа. В частности, малоизученными продолжают быть механизмы функционирования в ходе беременности ретротранспозонов, не содержащих длинных концевых повторов (non-LTR ретротранспозонов). Глубокое понимание этих процессов необходимо для прояснения нарушений регуляции в плаценте при больших акушерских синдромах. В данном обзоре рассматривается вклад мобильных элементов в функционирование генома человека, в частности их влияние на экспрессию генов, в контексте беременности и развития плаценты.

1. Arnold L.L., Doherty T.M., Flor A.W., Simon J.A., Chou J.Y., Chan W.Y., Mansfield B.C. Pregnancy-specific glycoprotein gene expression in recurrent aborters: a potential correlation to interleukin-10 expression. Am J Reprod Immunol. 1999;41(3):174-182. doi: 10.1111/j.1600-0897.1999.tb00530.x

2. Ashley J., Cordy B., Lucia D., Fradkin L.G., Budnik V., Thomson T. Retrovirus-like gag protein arc1 binds RNA and traffics across synaptic boutons. Cell. 2018;172(1-2):262-274.e11. doi: 10.1016/j.cell.2017.12.022

3. Barsh G.S., Seeburg P.H., Gelinas R.E. The human growth hormone gene family: structure and evolution of the chromosomal locus. Nucleic Acids Res. 1983;11(12):3939-3958. doi: 10.1093/nar/11. 12.3939

4. Belshaw P.J., Walsh C.T., Stachelhaus T. Aminoacyl-CoAs as probes of condensation domain selectivity in nonribosomal peptide synthesis. Science. 1999;284(5413):486-489. doi: 10.1126/science.284.5413.486

5. Benson D.A., Karsch-Mizrachi I., Lipman D.J., Ostell J., Sayers E.W. GenBank. Nucleic Acids Res. 2009;37(D1):D26-D31. doi: 10.1093/nar/gkn723

6. Bi S., Gavrilova O., Gong D.W., Mason M.M., Reitman M. Identification of a placental enhancer for the human leptin gene. J Biol Chem. 1997;272(48):30583-30588. doi: 10.1074/jbc.272.48.30583

7. Bourque G., Burns K.H., Gehring M., Gorbunova V., Seluanov A., Hammell M., Imbeault M., Izsvák Z., Levin H.L., Macfarlan T.S., Mager D.L., Feschotte C. Ten things you should know about transposable elements. Genome Biol. 2018;19(1):199. doi: 10.1186/s13059-018-1577-z

8. Brosius J.P. Analyses and interventions: anthropological engagements with environmentalism. Curr Anthropol. 1999;40(3):277-309. doi: 10.1086/200019

9. Brosius J., Gould S.J. On “genomenclature”: a comprehensive (and respectful) taxonomy for pseudogenes and other “junk DNA”. Proc Natl Acad Sci USA. 1992;89(22):10706-10710. doi: 10.1073/pnas.89.22.10706

10. Buttler C.A., Chuong E.B. Emerging roles for endogenous retroviruses in immune epigenetic regulation. Immunol Rev. 2022;305(1): 165-178. doi: 10.1111/imr.13042

11. Chesnokova E., Beletskiy A., Kolosov P. The role of transposable elements of the human genome in neuronal function and pathology. Int J Mol Sci. 2022;23(10):5847. doi: 10.3390/ijms23105847

12. Choudhary M.N.K., Friedman R.Z., Wang J.T., Jang H.S., Zhuo X., Wang T. Co-opted transposons help perpetuate conserved higher-order chromosomal structures. Genome Biol. 2020;21(1):16. doi: 10.1186/s13059-019-1916-8

13. Chuong E.B., Elde N.C., Feschotte C. Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science. 2016;351(6277):1083-1087. doi: 10.1126/science.aad5497

14. Clark M.B., Jänicke M., Gottesbühren U., Legge M., Poole E.S., Warren P.T. Mammalian gene PEG10 expresses two reading frames by high efficiency –1 frameshifting in embryonic-associated tissues. J Biol Chem. 2007;282(52):37359-37369. doi: 10.1074/jbc.M705676200

15. Criscione S.W., Theodosakis N., Micevic G., Cornish T.C., Burns K.H., Neretti N., Rodić N. Genome-wide characterization of human L1 antisense promoter-driven transcripts. BMC Genomics. 2016;17: 463. doi: 10.1186/s12864-016-2800-5

16. de Koning A.P.J., Gu W., Castoe T.A., Batzer M.A., Pollock D.D. Repetitive elements may comprise over two-thirds of the human genome. PLoS Genet. 2011;7(12):e1002384. doi: 10.1371/journal.pgen.1002384

17. Doolittle W.F., Sapienza C. Selfish genes, the phenotype paradigm and genome evolution. Nature. 1980;284(5757):601-603. doi: 10.1038/284601a0

18. Dunn-Fletcher C.E., Muglia L.M., Pavlicev M., Wolf G., Sun M.A., Hu Y.C., Huffman E., … Swaggart K.A., Lamm K.Y.B., Jones H., Macfarlan T.S., Muglia L.J. Anthropoid primate-specific retroviral element THE1B controls expression of CRH in placenta and alters gestation length. PLoS Biol. 2018;16:e2006337. doi: 10.1371/journal.pbio.2006337

19. Ehrlich M., Gama-Sosa M.A., Huang L.-H., Midgett R.M., Kuo K.C., McCune R.A., Gehrke C. Amount and distribution of 5-methylcytosine in human DNA from different types of tissues or cells. Nucleic Acids Res. 1982;10(8):2709-2721. doi: 10.1093/nar/10.8.2709

20. Frost J.M., Amante S.M., Okae H., Jones E.M., Ashley B., Lewis R.M., Cleal J.K., Caley M.P., Arima T., Maffucci T., Branco M.R. Regulation of human trophoblast gene expression by endogenous retroviruses. Nat Struct Mol Biol. 2023;30(4):527-538. doi: 10.1038/s41594-023-00960-6

21. Gellersen B., Brosens I.A., Brosens J.J. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445-453. doi: 10.1055/s-2007-991042

22. Grow E.J., Flynn R.A., Chavez S.L., Bayless N.L., Wossidlo M., Wesche D.J., Martin L., Ware C.B., Blish C.A., Chang H.Y., Pera R.A., Wysocka J. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature. 2015;522(7555):221-225. doi: 10.1038/nature14308

23. Haig D. Placental growth hormone-related proteins and prolactin-related proteins. Placenta. 2008;29:S36-S41. doi: 10.1016/j.placenta.2007.09.010

24. Hamilton W.J., Boyd J.D. Development of the human placenta in the first three months of gestation. J Anat. 1960;94(3):297-328

25. Honda T. Links between human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma. Front Chem. 2016;4:21. doi: 10.3389/fchem.2016.00021

26. Hoyt S.J., Storer J.M., Hartley G.A., Grady P.G.S., Gershman A., de Lima L.G., Limouse C., … Eichler E.E., Phillippy A.M., Timp W., Miga K.H., O’Neill R.J. From telomere to telomere: the transcriptional and epigenetic state of human repeat elements. Science. 2022; 376(6588):eabk3112. doi: 10.1126/science.abk3112

27. Jachowicz J.W., Bing X., Pontabry J., Bošković A., Rando O.J., Torres-Padilla M.-E. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat Genet. 2017; 49(10):1502-1510. doi: 10.1038/ng.3945

28. Johnson W.E. Origins and evolutionary consequences of ancient endogenous retroviruses. Nat Rev Microbiol. 2019;17(6):355-370. doi: 10.1038/s41579-019-0189-2

29. Kentepozidou E., Aitken S.J., Feig C., Stefflova K., Ibarra-Soria X., Odom D.T., Roller M., Flicek P. Clustered CTCF binding is an evolutionary mechanism to maintain topologically associating domains. Genome Biol. 2020;21(1):5. doi: 10.1186/s13059-019-1894-x

30. Kim A., Terzian C., Santamaria P., Pelisson A., Purd’homme N., Bucheton A. Retroviruses in invertebrates: the gypsy retrotransposon is apparently an infectious retrovirus of Drosophila melanogaster. Proc Natl Acad Sci USA. 1994;91(4):1285-1289. doi: 10.1073/pnas.91.4.1285

31. Kitazawa M., Tamura M., Kaneko-Ishino T., Ishino F. Severe damage to the placental fetal capillary network causes mid-to late fetal lethality and reductionin placental size in Peg11/Rtl1 KO mice. Genes Cells. 2017;22(2):174-188. doi: 10.1111/gtc.12465

32. Kojima K.K. Human transposable elements in Repbase: genomic footprints from fish to humans. Mob DNA. 2018;9:2. doi: 10.1186/s13100-017-0107-y

33. Kramerov D.A., Vassetzky N.S. SINEs. Wiley Interdiscip Rev RNA. 2011;2(6):772-786. doi: 10.1002/wrna.91

34. Kruse K., Díaz N., Enriquez-Gasca R., Gaume X., Torres-Padilla M.- E., Vaquerizas J.M. Transposable elements drive reorganisation of 3D chromatin during early embryogenesis. BioRxiv. 2019. doi: 10.1101/523712

35. Lanciano S., Philippe C., Sarkar A., Pratella D., Domrane C., Doucet A.J., van Essen D., Saccani S., Ferry L., Defossez P.A., Cristofari G. Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites. Cell Genom. 2024;4(2):100498. doi: 10.1016/j.xgen.2024.100498

36. Lee M., Ahmad S.F., Xu J. Regulation and function of transposable elements in cancer genomes. Cell Mol Life Sci. 2024;81(1):157. doi: 10.1007/s00018-024-05195-2

37. Li Y., Moretto-Zita M., Leon-Garcia S., Parast M.M. p63 inhibits extravillous trophoblast migration and maintains cells in a cytotrophoblast stem cell-like state. Am J Pathol. 2014;184(12):3332-3343. doi: 10.1016/j.ajpath.2014.08.006

38. Lou C., Goodier J.L., Qiang R.A. Potential new mechanism for pregnancy loss: considering the role of LINE-1 retrotransposons in early spontaneous miscarriage. Reprod Biol Endocrinol. 2020;18(1):6. doi: 10.1186/s12958-020-0564-x

39. Lu J.Y., Shao W., Chang L., Yin Y., Li T., Zhang H., Hong Y., … Liu W., Yan P., Ramalho-Santos M., Sun Y., Shen X. Genomic repeats categorize genes with distinct functions for orchestrated regulation. Cell Rep. 2020;30(10):3296-3311. doi: 10.1016/j.celrep.2020.02.048

40. Lynch V.J., Leclerc R.D., May G., Wagner G.P. Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat Genet. 2011;43(11):1154-1159. doi: 10.1038/ng.917

41. Lynch V.J., Nnamani M.C., Kapusta A., Brayer K., Plaza S.L., Mazur E.C., Emera D., … Young S.L., Lieb J.D., DeMayo F.J., Feschotte C., Wagner G.P. Ancient transposable elements transformed the uterine regulatory landscape and transcriptome during the evolution of mammalian pregnancy. Cell Rep. 2015;10(4):551-561. doi: 10.1016/j.celrep.2014.12.052

42. Macaulay E.C., Weeks R.J., Andrews S., Morison I.M. Hypomethylation of functional retrotransposon-derived genes in the human placenta. Mamm Genome. 2011;22(11-12):722-735. doi: 10.1007/s00335-011-9355-1

43. Magariños M.P., Sánchez-Margalet V., Kotler M., Calvo J.C., Varone C.L. Leptin promotes cell proliferation and survival of trophoblastic cells. Biol Reprod. 2007;76(2):203-210. doi: 10.1095/biolreprod.106.051391

44. Mangeney M., Renard M., Schlecht-Louf G., Bouallaga I., Heidmann O., Letzelter C., Richaud A., Ducos B., Heidmann T. Placental syncytins: genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins. Proc Natl Acad Sci USA. 2007;104(51):20534-20539. doi: 10.1073/pnas.0707873105

45. Mano Y., Kotani T., Shibata K., Matsumura H., Tsuda H., Sumigama S., Yamamoto E., Iwase A., Senga T., Kikkawa F. The loss of endoglin promotes the invasion of extravillous trophoblasts. Endocrinology. 2011;152(11):4386-4394. doi: 10.1210/en.2011-1088

46. Modzelewski A.J., Chong J.G., Wang T., He L. Mammalian genome innovation through transposon domestication. Nat Cell Biol. 2022; 24(9):1332-1340. doi: 10.1038/s41556-022-00970-4

47. Mustafin R.N. Functional dualism of transposon transcripts in evolution of eukaryotic genomes. Russ J Dev Biol. 2018;49:339-355. doi: 10.1134/S1062360418070019

48. Nelson P.N., Carnegie P.R., Martin J., Davari Ejtehadi H., Hooley P., Roden D., Rowland-Jones S., Warren P., Astley J., Murray P.G. Demystified. Human endogenous retroviruses. Mol Pathol. 2003; 56(1):11-18. doi: 10.1136/mp.56.1.11

49. Novakovic B., Saffery R. Placental pseudo-malignancy from a DNA methylation perspective: unanswered questions and future directions. Front Genet. 2013;4:285. doi: 10.3389/fgene.2013.00285

50. Ohnuki M., Tanabe K., Sutou K., Takahashi K. Dynamic regulation of human endogenous retroviruses mediates factor-induced reprogramming and differentiation potential. Proc Natl Acad Sci USA. 2014;111(34):12426-12431. doi: 10.1073/pnas.1413299111

51. Ono R., Nakamura K., Inoue K., Naruse M., Usami T., Wakisaka-Saito N., Hino T., … Miki H., Kohda T., Ogura A., Yokoyama M., Kaneko-Ishino T. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat Genet. 2006;38(1):101-106. doi: 10.1038/ng1699

52. Oomen M.E., Rodriguez-Terrones D., Kurome M., Zakhartchenko V., Mottes L., Simmet K., Noll C., … Savatier P., Göke J., Wolf E., Kaessmann H., Torres-Padilla M. An atlas of transcription initiation reveals regulatory principles of gene and transposable element expression in early mammalian development. Cell. 2025;188(4): 1156-1174.e20. doi: 10.1016/j.cell.2024.12.013

53. Percharde M., Lin C.-J., Yin Y., Guan J., Peixoto G.A., Bulut-Karslioglu A., Biechele S., Huang B., Shen X., Ramalho-Santos M. A LINE1-nucleolin partnership regulates early development and ESC identity. Cell. 2018;174(2):391-405.e19. doi: 10.1016/j.cell.2018.05.043

54. Pérez-Pérez A., Toro A., Vilariño-García T., Maymó J., Guadix P., Dueñas J., Fernández-Sánchez M., Varone C., Sánchez-Margalet V. Leptin action in normal and pathological pregnancies. J Cell Mol Med. 2018;22(2):716-727. doi: 10.1111/jcmm.13369

55. Pötgens A.J.G., Schmitz U., Bose P., Versmold A., Kaufmann P., Frank H.-G. Mechanisms of syncytial fusion : a review. Placenta. 2002;23:S107-S113. doi: 10.1053/plac.2002.0772

56. Price E.M., Cotton A.M., Peñaherrera M.S., McFadden D.E., Kobor M.S., Robinson W. Different measures of “genome-wide” DNA methylation exhibit unique properties in placental and somatic tissues. Epigenetics. 2012;7(6):652-663. doi: 10.4161/epi.20221

57. Rao S.S.P., Huang S.C., Glenn St Hilaire B., Engreitz J.M., Perez E.M., Kieffer-Kwon K.R., Sanborn A.L., … Schlick T., Bernstein B.E., Casellas R., Lander E.S., Aiden E.L. Cohesin loss eliminates all loop domains. Cell. 2017;171(2):305-320.e24. doi: 10.1016/j.cell.2017.09.026

58. Reiss D., Zhang Y., Mager D.L. Widely variable endogenous retroviral methylation levels in human placenta. Nucleic Acids Res. 2007; 35(14):4743-4754. doi: 10.1093/nar/gkm455

59. Riege K., Kretzmer H., Sahm A., McDade S.S., Hoffmann S., Fischer M. Dissecting the DNA binding landscape and gene regulatory network of p63 and p53. eLife. 2020;9:e63266. doi: 10.7554/eLife.63266

60. Robinson W.P., Price E.M. The human placental methylome. Cold Spring Harb Perspect Med. 2015;5(5):a023044. doi: 10.1101/cshperspect.a023044

61. Rondinone O., Murgia A., Costanza J., Tabano S., Camanni M., Corsaro L., Fontana L., … Ferrazzi E., Bosari S., Gentilini D., Sirchia S.M., Miozzo M. Extensive placental methylation profiling in normal pregnancies. Int J Mol Sci. 2021;22(4):2136. doi: 10.3390/ijms22042136

62. Rudert F., Zimmermann W., Thompson J.A. Intra- and interspecies analyses of the carcinoembryonic antigen (CEA) gene family reveal independent evolution in primates and rodents. J Mol Evol. 1989;29(2):126-134. doi: 10.1007/BF02100111

63. Santoni F.A., Guerra J., Luban J. HERV-H RNA is abundant in human embryonic stem cells and a precise marker for pluripotency. Retrovirology. 2012;9:111. doi 10.1186/1742-4690-9-111

64. Schmid D., Bucher P. MER41 repeat sequences contain inducible STAT1 binding sites. PLoS One. 2010;5(7):e11425. doi: 10.1371/journal.pone.0011425

65. Sekita Y., Wagatsuma H., Nakamura K., Ono R., Kagami M., Wakisaka N., Hino T., … Ogura A., Ogata T., Yokoyama M., Kaneko-Ishino T., Ishino F. Role of retrotransposon-derived imprinted gene, Rtl1, in the feto-maternal interface of mouse placenta. Nat Genet. 2008;40(2):243-248. doi: 10.1038/ng.2007.51

66. Shimode S. Acquisition and exaptation of endogenous retroviruses in mammalian placenta. Biomolecules. 2023;13(10):1482. doi: 10.3390/biom13101482

67. Simonti C.N., Pavličev M., Capra J.A. Transposable element exaptation into regulatory regions is rare, influenced by evolutionary age, and subject to pleiotropic constraints. Mol Biol Evol. 2017;34(11): 2856-2869. doi: 10.1093/molbev/msx219

68. Slotkin R.K., Martienssen R. Transposable elements and the epigenetic regulation of the genome. Nat Rev Genet. 2007;8(4):272-285. doi: 10.1038/nrg2072

69. Song S.U., Gerasimova T., Kurkulos M., Boeke J.D., Corces V.G. An Env-like protein encoded by a Drosophila retroelement: evidence that gypsy is an infectious retrovirus. Genes Dev. 1994;8(17): 2046-2057. doi: 10.1101/gad.8.17.2046

70. Su D., Wang X., Campbell M.R., Song L., Safi A., Crawford G.E., Bell D.A. Interactions of chromatin context, binding site sequence content, and sequence evolution in stress-induced p53 occupancy and transactivation. PLoS Genet. 2015;11(1):e1004885. doi: 10.1371/journal.pgen.1004885

71. Sugimoto J., Sugimoto M., Bernstein H., Jinno Y., Schust D. A novel human endogenous retroviral protein inhibits cell-cell fusion. Sci Rep. 2013;3:1462. doi: 10.1038/srep01462

72. Sun M., Wolf G., Wang Y., Senft A.D., Ralls S., Jin J., Dunn-Fletcher C.E., Muglia L.J., Macfarlan T.S. Endogenous retroviruses drive lineage-specific regulatory evolution across primate and rodent placentae. Mol Biol Evol. 2021;38(11):4992-5004. doi: 10.1093/molbev/msab223

73. Towler C.M., Horne C.H.W., Jandial V., Campbell D.M., MacGillivray I. Plasma levels of pregnancy-specific βl-glycoprotein in complicated pregnancies. Br J Obstet Gynaecol. 1977;84(4):258-263. doi: 10.1111/j.1471-0528.1977.tb12573.x

74. van de Lagemaat L.N., Landry J.R., Mager D.L., Medstrand P. Transposable elements in mammals promote regulatory variation and diversification of genes with specialized functions. Trends Genet. 2003;19(10):530-536. doi: 10.1016/j.tig.2003.08.004

75. Vasilyev S.A., Tolmacheva E.N., Vasilyeva O.Yu., Markov A.V., Zhigalina D.I., Zatula L.A., Lee V.A., Serdyukova E.S., Sazhenova E.A., Nikitina T.V., Kashevarova A.A., Lebedev I.N. LINE-1 retrotransposon methylation in chorionic villi of first trimester miscarriages with aneuploidy. J Assist Reprod Genet. 2021;38(1):139-149. doi: 10.1007/s10815-020-02003-1

76. Vietri M., Schink K.O., Campsteijn C., Wegner C.S., Schultz S.W., Christ L., Thoresen S.B., Brech A., Raiborg C., Stenmark H. Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. Nature. 2015;522(7555):231-235. doi: 10.1038/nature14408

77. West R.C., Ezashi T., Schoolcraft W.B., Yuan Y. Beyond fusion: a novel role for ERVW-1 in trophoblast proliferation and type I interferon receptor expression. Placenta. 2022;126:150-159. doi: 10.1016/j.placenta.2022.06.012

78. Wicker T., Sabot F., Hua-Van A., Bennetzen J.L., Capy P., Chalhoub B., Flavell A., Leroy P., Morgante M., Panaud O., Paux E., SanMiguel P., Schulman A.H. A unified classification system for eukaryotic transposable elements. Nat Rev Genet. 2007;8(12):973-982. doi 10.1038/nrg2165

79. Xia B., Zhang W., Zhao G., Zhang X., Bai J., Brosh R., Wudzinska A., … Dasen J.S., Maurano M.T., Kim S.Y., Boeke J.D., Yanai I. On the genetic basis of tail-loss evolution in humans and apes. Nature. 2024;626(8001):1042-1048. doi: 10.1038/s41586-024-07095-8

80. Yu Y., He J.‐H., Hu L.-L., Jiang L.-L., Fang L., Yao G.‐D., Wang S.‐ J., … Shang T., Sato Y., Kawamura K., Hsueh A.J.W., Sun Y.‐P. Placensin is a glucogenic hormone secreted by human placenta. EMBO Rep. 2020;21(6):e49530. doi: 10.15252/embr.201949530

81. Zimmermann W., Kammerer R. The immune-modulating pregnancy-specific glycoproteins evolve rapidly and their presence correlates with hemochorial placentation in primates. BMC Genomics. 2021; 22(1):128. doi: 10.1186/s12864-021-07413-8