Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute12195310.23868/202104001ArticlesСтатьиReview ArticleInvolvement of transposons in epigenetic regulation of embryogenesisВклад транспозонов в эпигенетическую регуляцию эмбриогенезаMustafinR. NМустафинР. Нruji79@mail.ruBashkir State Medical UniversityБашкирский государственный медицинский университет15032021161VOL 16, NO1 (2021)ТОМ 16, №1 (2021)101416012023Copyright ©; 2021, Eco-VectorCopyright ©; 2021, Эко-Вектор2021Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/121953

The systems that control DNA methylation and histone modifications in embryonic development are still considered unknown, although their study is promising for the development of stem cell genetics. This review article is devoted to the description of evidence that the drivers of changes in epigenetic factors of stem cells in their successive divisions are species-specific patterns of activation of transposable elements formed in evolution. These patterns are due to the sensitivity of transposons to the influence of the microenvironment and environmental factors, as well as the functioning of their processed transcripts as noncoding RNAs. A large amount of evidence has been accumulated that many protein-coding genes originate from transposable elements, including those involved in DNA methylation and histone modification. Moreover, transposons are key sources of binding sites for transcription factors, promoters, enhancers, silencers, insulators, as well as small and long non-coding RNAs that have an epigenetic effect on gene expression at the transcriptional and post-transcriptional levels. In evolution, transposons were the sources of origin for spliceoso-mal introns and components of the spliceosome, alternative sites and regulators of splicing. The identification of specific transposons that serve as drivers of stem cells at certain stages can become the basis for their optimal control using noncoding RNAs.

Механизмы, управляющие метилированием ДНК и модификациями гистонов в эмбриональном развитии, до сих пор считаются неизвестными, их раскрытие перспективно для развития генетики стволовых клеток. В обзорной статье представлены доказательства того, что драйверами эпигенетических изменений при дифференцировке клеток в их последовательных делениях служат сформированные в эволюции видоспецифические паттерны активаций транспозонов. Это связано с чувствительностью мобильных элементов к воздействиям микроокружения и факторов среды, а также функционированием их процессированных транскриптов в качестве некодирующих РНК. В ходе эволюции от транспозонов произошли многие белок-кодирующие гены, в том числе участвующие в метилировании ДНК и модификации гистонов. Кроме того, мобильные элементы являются ключевыми источниками сайтов связывания с транскрипционными факторами, промоторов, энхансеров, сайленсеров, инсуляторов, а также малых и длинных некодирующих РНК, оказывающих эпигенетическое воздействие на экспрессию генов на транскрипционном и посттранскрипционном уровнях. В ходе эволюции от транспозонов произошли сплайсосомные интроны и компоненты сплайсосомы, альтернативные сайты и регуляторы сплайсинга. Выявление специфических транспозонов, которые служат драйверами стволовых клеток на определенных стадиях, может стать основой для оптимального управления клетками при помощи некодирующих РНК.

DNA methylationhistone modificationsnoncoding RNAsstem cellschromatinepigenetic regulationметилирование ДНКмодификации гистоновнекодирующие РНКстволовые клеткихроматинэпигенетическая регуляцияPatel T., Hobert O. Coordinated control of terminal differentiation and restriction of cellular plasticity. eLife 2017; 6: e24100.Zakrzewski W., Dobrzynski M., Szymonowicz M. et al. Stem cells: past, present, and future. Stem Cell Res. Ther. 2019; 10(1): 68.Gerdes P., Richardson S.R., Mager D.L. et al. Transposable elements in the mammalian embryo: pioneers surviving through stealth and service. Genome Biol. 2016; 17: 100-6.Smith Z.D., Chan M.M., Humm K.C. et al. DNA methylation dynamics of the human preimplantation embryo. Nature 2014; 511(7511): 611-5.Klawitter S., Fuchs N.V., Upton K.R. et al. Reprogramming triggers endogenous L1 and Alu retrotransposition in human induced pluripotent stem cells. Nat. Commun. 2016; 7: 10286-91.Wissing S., Munoz-Lopez M., Macia A. et al. Reprogramming somatic cells into iPS cell activates LINE-1 retroelement mobility. Hum. Mol. Genet. 2012; 21(1): 208-18.Alzohairy A.M., Gyulai G., Jansen R.K. et al. Transposable elements domesticated and neofunctionalized by eukaryotic genomes. Plasmid 2013; 69: 1-5.Мустафин Р.Н., Хуснутдинова Э.К. Роль обратной транскриптазы в возникновении жизни. Биохимия 2019; 84(8): 1099-114Grow E.J., Flynn R.A., Shawn L.C. et al. Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells. Nature 2015; 522(7555): 221-5.Gao L., Wu K., Liu Z. et al. Chromatin Accessibility Landscape in Human Early Embryos and Its Association with Evolution. Cell 2018; 173: 248-59.Macfarlan T.S., Gifford W.D., Driscoll S. et al. ES cell potency fluctuates with endogenous retrovirus activity. Nature 2012; 487: 57-63.Jachowicz J.W., Bing X., Pontabry J. et al. LINE-1 activation after fertilization regulates global chromatin accessibility in the early mouse embryo. Nat. Genet. 2017; 49: 1502-10.Wang J., Li X., Wang L. et al. A novel long intergenic noncoding RNA indispensable for the cleavage of mouse two-cell embryos. EMBO Rep. 2016; 17: 1452-60.Honson D.D., Macfarlan T.S. A lncRNA-like Role for LINE1s in Development. Dev. Cell 2018; 46(20): 132-4.Garcia-Perez J.L., Marchetto M.C., Muotri A.R. et al. LINE-1 retrotransposition in human embryonic stem cells. Hum. Mol. Genet. 2007; 16(13): 1569-77.Macia A., Munoz-Lopez M., Cortes J.L. et al. Epigenetic control of retrotransposons expression in human embryonic stem cells. Mol. Cell Biol. 2011; 31(2): 300-6.Lee K.H., Yee L., Lim D. et al. Temporal and spatial rearrangements of a repetitive element array on C57BL/6J mouse genome. Exp. Mol. Pathol. 2015; 98(3): 439-45.Marchetto M.C., Narvaiza I., Denli A.M. et al. Differential L1 regulation in pluripotent stem cells of humans and apes. Nature 2013; 503: 525-9.Pavlicev M., Hiratsuka K., Swaggart K.A. et al. Detecting endogenous retrovirus-driven tissue-specific gene transcription. Genome Biol. Evol. 2015; 7: 1082-7.Мустафин Р.Н., Хуснутдинова Э.К. Стресс-индуцированная активация транспозонов в экологическом морфогенезе. Вавиловский журнал генетики и селекции 2019; 23(4): 380-9.De Souza F.S., Franchini L.F., Rubinstein M. Exaptation of transposable elements into novel cis-regulatory elements: is the evidence always strong. Mol. Biol. Evol. 2013; 30: 1239-51.Kapusta A., Kronenberg Z., Lynch V.J. et al. Transposable elements are major contributors to the origin, diversification, and regulation of vertebrate long noncoding RNAs. PLoS Genet. 2013; 9: e1003470.Borchert G.M., Holton N.W., Williams J.D. et al. Comprehensive analysis of microRNA genomic loci identifies pervasive repetitive-element origins. Mobile Genetic Elements 2011; 1: 8-17.Gim J., Ha H., Ahn K. et al. Genome-Wide Identification and Classification of microRNAs derived from repetitive elements. Genomic Inform. 2014; 12: 261-7.Lee H., Huh J., Kim H. Bioinformatics Analysis of Evolution and Human Disease Related Transposable Element-Derived microRNAs. Life (Basel) 2020; 10(6): 95.Qin S., Jin P., Zhou X. et al. The Role of Transposable Elements in the Origin and Evolution of MicroRNAs in Human. PLoS One 2015; 10(6): e0131365.Wei G., Qin S., Li W. et al. MDTE DB: a database for microRNAs derived from Transposable element. IEEE/ACM Trans. Comput. Biol. Bioinform. 2016; 13: 1155-60.Murashov A.K. RNAi and MicroRNA - Mediated Gene Regulation in Stem Cells. Methods Mol. Biol. 2017; 1622: 15-25.Ong S., Lee W.H., Kodo K. et al. MicroRNA-mediated regulation of differentiation and transdifferentiation in stem cells. Adv. Drug Deliv. Rev. 2015; 88: 3-5.Li N., Long B., Han W. et al. microRNAs: important regulators of stem cells. Stem Cell Res. Ther. 2017; 8(1): 110.Long Y., Wang X., Youmans D.T. et al. How do lncRNAs regulate transcription. Sci. Adv. 2017; 3: eaao2110.Lu X., Sachs F., Ramsay L. et al. The retrovirus HERVH is a long noncoding RNA required for human embryonic stem cell identity. Nat. Struct. Mol. Biol. 2014; 21: 423-5.Samantarrai D., Dash S., Chhetri B. et al. Genomic and epigenomic cross-talks in the regulatory landscape of miRNAs in breast cancer. Mol. Cancer Res. 2013; 11: 315-8.Dlakic M., Mushegian A. Prp8, the Pivotal Protein of the Spliseo-somal Catalytic Center, Evolved From a Retroelement - Encoded Reverse Transcriptase. RNA 2011; 17(5): 799-808.Novikova O., Belfort M. Mobile Group II Introns as Ancestral Eukaryotic Elements. Trends Genet. 2017; 33: 773-83.Dumesic P.A., Madhani H.D. The spliceosome as a transposon sensor. RNA Biol. 2013; 10: 1653-60.Lei H., Vorechovsky I. Identification of splicing silencers and enhancers in sense Alus: a role for pseudoacceptors in splice site repression. Mol. Cell Biol. 2005; 25(16); 6912-20.Pastor T., Talotti G., Lewandowska M.A. et al. An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM. Nucleic Acids Res. 2009; 37(21): 7258-67.Schmitz J., Brosius J. Exonization of transposed elements: A challenge and opportunity for evolution. Biochimie 2011; 93: 1928-34.Luco R.F., Allo M., Schor I.E. et al. Epigenetics in alternative pre-mRNA splicing. Cell 2011; 144(1): 16-26.Johnson R., Guigo R. The RIDL hypothesis: transposable elements as functional domains of long noncoding rNas. RNA 2014; 20: 959-66.Duan C.G., Wang X., Pan L. et al. A pair of transposon-derived proteins function in a histone acetyltransferase complex for active DNA demethylation. Cell Res. 2017; 27(2): 226-30.Percharde M., Lin C.J., Yin Y. et al. A LINE1-Nucleolin partnership regulates early development and ESC identity. Cell 2018; 174: 391-5.Khowutthitham S., Ngamphiw C., Wanichnopparat W. et al. Intragenic long interspersed element-1 sequences promote promoter hypermethylation in lung adenocarcinoma, multiple myeloma and prostate cancer. Genes and Genomics 2012; 34(5): 517-8.Lapp H.E., Hunter R.G. The dynamic genome: transposons and environmental adaptation in the nervous system. Epigenomics 2016; 8: 237-9.Lynch V.J., Leclerc R.D., May G. et al. Transposon-mediated rewiring of gene regulatory networks contributed to the evolution of pregnancy in mammals. Nat. Gent. 2011; 43(11): 1154-9.Lv C., Li F., Li X. et al. MiR-31 promotes mammary stem cell expansion and breast tumorigenesis by suppressing Wnt signaling antagonists. Nat. Commun. 2017; 8(1): 1036.Wong N.W., Chen Y., Chen S. et al. OncomiR: and online resource for exploring pan-cancer microRNA dysregulation. Bioinformatics 2018; 34: 713-5.