Genes & CellsGenes & CellsГены и КлеткиGenes and Cells2313-18292500-2562Human Stem Cells Institute12057510.23868/gc120575ArticlesСтатьиReview ArticleEditing of DNA epigenetic modificationsРЕДАКТИРОВАНИЕ ЭПИГЕНЕТИЧЕСКИХ МОДИФИКАЦИЙ ДНКGrinI. RГринИ. РPetrovaD. VПетроваД. ВZharkovD. OЖарковД. ОInstitute of Chemical Biology and Fundamental Medicine, the Siberian Branch of the Russian Academy of SciencesФГБНУ «Институт химической биологии и фундаментальной медицины СО РАН»National Research University Novosibirsk State UniversityНовосибирский национальный исследовательский государственный университет15062016112VOL 11, NO2 (2016)ТОМ 11, №2 (2016)536005012023Copyright ©; 2016, Eco-VectorCopyright ©; 2016, Эко-Вектор2016Eco-VectorЭко-Векторhttps://genescells.ru/2313-1829/article/view/120575

Геномное редактирование в последние годы прочно вошло в арсенал методов молекулярной и клеточной биологии. Однако у высших эукариот огромную роль в формировании фенотипа клеток и организма в целом играет также состояние эпигенома - системы ковалентных модификаций ДНК и связанных с ней белков, регулирующих экспрессию генов. Методы редактирования эпигенома только начинают появляться, и в сочетании с технологиями геномного редактирования должны обеспечить более надежный контроль состояния изменяемых клеток. В обзоре освещены механизмы метилирования и активного деметилирования ДНК в клетках высших организмов и способы их применения для направленного изменения состояния эпигенома.

Cas9эпигенетика5-метилцитозинДНК-метилтрансферазыоксидативные деметилазырепарация ДНКцинковые пальцыTAL-эффекторыLee T.-f., Zhai J., Meyers B.C. Conservation and divergence in eukaryotic DNA methylation. PNAS USA 2010; 107: 9027-8.Zemach A., Zilberman D. Evolution of eukaryotic DNA methylation and the pursuit of safer sex. Curr. Biol. 2010; 20: R780-R5.Deaton A.M., Bird A. CpG islands and the regulation of transcription. Genes Dev. 2011; 25: 1010-22.Weber M., Schübeler D. Genomic patterns of DNA methylation: Targets and function of an epigenetic mark. Curr. Opin. Cell Biol. 2007; 19: 273-80.Ballestar E., Wolffe A.P. Methyl-CpG-binding proteins. Eur. J. Biochem. 2001; 268: 1-6.Baubec T., Ivanek R., Lienert F., Schübeler D. Methylation-dependent and -independent genomic targeting principles of the MBD protein family. Cell 2013; 153: 480-92.Boyes J., Bird A. Repression of genes by DNA methylation depends on CpG density and promoter strength: Evidence for involvement of a methyl-CpG binding protein. EMBO J. 1992; 11: 327-33.Hsieh C.-L. Dependence of transcriptional repression on CpG methylation density. Mol. Cell. Biol. 1994; 14: 5487-94.Weber M., Hellmann I., Stadler M.B., Ramos L., Pääbo S., Rebhan M., Schübeler D. Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome. Nat. Genet. 2007; 39: 457-66.Singer M., Kosti I., Pachter L., Mandel-Gutfreund Y. A diverse epigenetic landscape at human exons with implication for expression. Nucleic Acids Res. 2015; 43: 3498-508.Branco M.R., Ficz G., Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat. Rev. Genet. 2011; 13: 7-13.Pastor W.A., Pape U.J., Huang Y. et al. Genome-wide mapping of 5-hydroxymethylcytosine in embryonic stem cells. Nature 2011; 473: 394-7.Yu M., Hon G.C., Szulwach K.E. et al. Base-resolution analysis of 5-hydroxymethylcytosine in the mammalian genome. Cell 2012; 149: 1368-80.Spruijt C.G., Gnerlich F., Smits A.H. et al. Dynamic readers for 5-(hydroxy)methylcytosine and its oxidized derivatives. Cell 2013; 152: 1146-59.Takai H., Masuda K., Sato T. et al. 5-Hydroxymethylcytosine plays a critical role in glioblastomagenesis by recruiting the CHTOP-methylosome complex. Cell Rep. 2014; 9: 48-60.Jurkowska R.Z., Jurkowski T.P., Jeltsch A. Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011; 12: 206-22.Chuang L.S.-H., Ian H.-I., Koh T.-W. et al. Human DNA-(cytosine-5) methyltransferase-PCNA complex as a target for p21WAF1. Science 1997; 277: 1996-2000.Iida T., Suetake I., Tajima S. et al. PCNA clamp facilitates action of DNA cytosine methyltransferase 1 on hemimethylated DNA. Genes Cells 2002; 7: 997-1007.Rountree M.R., Bachman K.E., Baylin S.B. DNMT1 binds HDAC2 and a new co-repressor, DMAP1, to form a complex at replication foci. Nat. Genet. 2000; 25: 269-77.Viré E., Brenner C., Deplus R. et al. The Polycomb group protein EZH2 directly controls DNA methylation. Nature 2006; 439: 871-4.Kato Y., Kaneda M., Hata K. et al. Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse. Hum. Mol. Genet. 2007; 16: 2272-80.Watanabe D., Suetake I., Tada T., Tajima S. Stage- and cell-specific expression of Dnmt3a and Dnmt3b during embryogenesis. Mech. Dev. 2002; 118: 187-90.Okano M., Bell D.W., Haber D.A., Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 1999; 99: 247-57.Aapola U., Shibuya K., Scott H.S. et al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics. 2000; 65: 293-8.Bourc'his D., Xu G.-L., Lin C.-S. et al. Dnmt3L and the establishment of maternal genomic imprints. Science 2001; 294: 2536-9.Jia D., Jurkowska R.Z., Zhang X. et al. Structure of Dnmt3a bound to Dnmt3L suggests a model for de novo DNA methylation. Nature 2007; 449: 248-51.Goll M.G., Kirpekar F., Maggert K.A. et al. Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2. Science 2006; 311: 395-8.Bheemanaik S., Reddy Y.V.R., Rao D.N. Structure, function and mechanism of exocyclic DNA methyltransferases. Biochem. J. 2006; 399: 177-90.Santos F., Peat J., Burgess H. et al. Active demethylation in mouse zygotes involves cytosine deamination and base excision repair. Epigenetics Chromatin 2013; 6: 39.Franchini D.-M., Schmitz K.-M., Petersen-Mahrt S.K. 5-Methylcytosine DNA demethylation: More than losing a methyl group. Annu. Rev. Genet. 2012; 46: 419-41.Tahiliani M., Koh K.P., Shen Y. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009; 324: 930-5.He Y.-F., Li B.-Z., Li Z. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 2011; 333: 1303-7.Ito S., Shen L., Dai Q. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 2011; 333: 1300-3.Moran-Crusio K., Reavie L., Shih A. et al. Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation. Cancer Cell 2011; 20: 11-24.Dawlaty M.M., Ganz K., Powell B.E. et al. Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. Cell Stem Cell 2011; 9: 166-75.Gu T.-P., Guo F., Yang H. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 2011; 477: 606-10.Conticello S.G. The AId/aP0BEC family of nucleic acid mutators. Genome Biol. 2008; 9: 229.Storb U., Stavnezer J. Immunoglobulin genes: Generating diversity with AID and UNG. Curr. Biol. 2002; 12: R725-R7.Popp C., Dean W., Feng S. et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 2010; 463: 1101-5.Kumar R., DiMenna L., Schrode N. et al. AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes. Nature 2013; 500: 89-92.Nabel C.S., Jia H., Ye Y. et al. AID/AP0BEC deaminases disfavor modified cytosines implicated in DNA demethylation. Nat. Chem. Biol. 2012; 8: 751-8.Wallace S.S. Base excision repair: A critical player in many games. DNA Repair. 2014; 19: 14-26.Barreto G., Schäfer A., Marhold J. et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 2007; 445: 671-5.Moréra S., Grin I., Vigouroux A. et al. Biochemical and structural characterization of the glycosylase domain of MBD4 bound to thymine and 5-hydroxymethyuracil-containing DNA. Nucleic Acids Res. 2012; 40: 9917-26.Sabag 0., Zamir A., Keshet I. et al. Establishment of methylation patterns in ES cells. Nat. Struct. Mol. Biol. 2014; 21: 110-2.Lucey M.J., Chen D., Lopez-Garcia J. et al. T:G mismatch-specific thymine-DNA glycosylase tTDG) as a coregulator of transcription interacts with SRC1 family members through a novel tyrosine repeat motif. Nucleic Acids Res. 2005; 33: 6393-404.Léger H., Smet-Nocca C., Attmane-Elakeb A. et al. A TDG/ CBP/RARa ternary complex mediates the retinoic acid-dependent expression of DNA methylation-sensitive genes. Genomics Prot. Bioinform. 2014; 12: 8-18.Tini M., Benecke A., Um S.-J. et al. Association of CBP/ p300 acetylase and thymine DNA glycosylase links DNA repair and transcription. Mol. Cell 2002; 9: 265-77.Cortazar D., Kunz C., Selfridge J. et al. Embryonic lethal phenotype reveals a function of TDG in maintaining epigenetic stability. Nature 2011; 470: 419-23.Li Y.-Q., Zhou P.-Z., Zheng X.-D. et al. Association of Dnmt3a and thymine DNA glycosylase links DNA methylation with base-excision repair. Nucleic Acids Res. 2007; 35: 390-400.Boland M.J., Christman J.K. Characterization of Dnmt3b:thymine-DNA glycosylase interaction and stimulation of thymine glycosylase-mediated repair by DNA methyltransferasets) and RNA. J. Mol. Biol. 2008; 379: 492-504.Grin I., Ishchenko A.A. An interplay of the base excision repair and mismatch repair pathways in active DNA demethylation. Nucleic Acids Res. doi: 10.1093/nar/gkw059.Herman J.G., Baylin S.B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 2003; 349: 2042-54.Hambach L., Ling K.-W., Pool J. et al. Hypomethylating drugs convert HA-1-negative solid tumors into targets for stem cell-based immunotherapy. Blood 2009; 113: 2715-22.Saunthararajah Y., Lavelle D., DeSimone J. DNA hypomethylating agents and sickle cell disease. Br. J. Haematol. 2004; 126: 629-36.Lienert F., Wirbelauer C., Som I. et al. Identification of genetic elements that autonomously determine DNA methylation states. Nat. Genet. 2011; 43: 1091-7.Yu D.-H., Waterland R.A., Zhang P. et al. Targeted p16Ink4a epimutation causes tumorigenesis and reduces survival in mice. J. Clin. Invest. 2014; 124: 3708-12.Hsiao S.-H., Lee K.-D., Hsu C.-C. et al. DNA methylation of the Trip10 promoter accelerates mesenchymal stem cell lineage determination. Biochem. Biophys. Res. Commun. 2010; 400: 305-12.Lee K.-D., Pai M.-Y., Hsu C.-C. et al. Targeted Casp8AP2 methylation increases drug resistance in mesenchymal stem cells and cancer cells. Biochem. Biophys. Res. Commun. 2012; 422: 578-85.Leu Y.-W., Huang T.H.-M., Hsiao S.-H. Epigenetic reprogramming of mesenchymal stem cells. Adv. Exp. Med. Biol. 2013; 754: 195-211.Teng I.-W., Hou P.-C., Lee K.-D. et al. Targeted methylation of two tumor suppressor genes is sufficient to transform mesenchymal stem cells into cancer stem/initiating cells. Cancer Res. 2011; 71: 4653-63.van der Gun B.T.F., Maluszynska-Hoffman M., Kiss A. et al. Targeted DNA methylation by a DNA methyltransferase coupled to a triple helix forming oligonucleotide to down-regulate the epithelial cell adhesion molecule. Bioconjug. Chem. 2010; 21: 1239-45.Xu G.-L., Bestor T.H. Cytosine methylation targetted to predetermined sequences. Nat. Genet. 1997; 17: 376-8.Carvin C.D., Parr R.D., Kladde M.P. Site-selective in vivo targeting of cytosine-5 DNA methylation by zinc-finger proteins. Nucleic Acids Res. 2003; 31: 6493-501.McNamara A.R., Hurd P.J., Smith A.E.F., Ford K.G. Characterisation of site - biased DNA methyltransferases: Specificity, affinity and subsite relationships. Nucleic Acids Res. 2002; 30: 3818-30.Smith A.E., Ford K.G. Specific targeting of cytosine methylation to DNA sequences in vivo. Nucleic Acids Res. 2007; 35: 740-54.Smith A.E., Hurd P.J., Bannister A.J., Kouzarides T., Ford K.G. Heritable gene repression through the action of a directed DNA methyltransferase at a chromosomal locus. J. Biol. Chem. 2008; 283: 9878-85.Nomura W., Barbas C.F., III In vivo site-specific DNA methylation with a designed sequence-enabled DNA methylase. J. Am. Chem. Soc. 2007; 129: 8676-7.Chaikind B., Kilambi K.P., Gray J.J., Ostermeier M. Targeted DNA methylation using an artificially bisected M.HhaI fused to zinc fingers. PLoS ONE. 2012; 7: e44852.Slaska-Kiss K., Timâr E., Kiss A. Complementation between inactive fragments of SssI DNA methyltransferase. BMC Mol. Biol. 2012; 13: 17.Meister G.E., Chandrasegaran S., Ostermeier M. An engineered split M.HhaI-zinc finger fusion lacks the intended methyltransferase specificity. Biochem. Biophys. Res. Commun. 2008; 377: 226-30.Chaikind B., Ostermeier M. Directed evolution of improved zinc finger methyltransferases. PLoS ONE. 2014; 9: e96931.Nunna S., Reinhardt R., Ragozin S., Jeltsch A. Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells. PLoS ONE. 2014; 9: e87703.Siddique A.N., Nunna S., Rajavelu A. et al. Targeted methylation and gene silencing of VEGF-A in human cells by using a designed Dnmt3a-Dnmt3L single-chain fusion protein with increased DNA methylation activity. J. Mol. Biol. 2013; 425: 479-91.Rivenbark A.G., Stolzenburg S., Beltran A.S. et al. Epigenetic reprogramming of cancer cells via targeted DNA methylation. Epigenetics 2012; 7: 350-60.Minczuk M., Papworth M.A., Kolasinska P. et al. Sequence-specific modification of mitochondrial DNA using a chimeric zinc finger methylase. PNAS USA 2006; 103: 19689-94.Valton J., Cabaniols J.-P., Galetto R. et al. fficient strategies for TALEN-mediated genome editing in mammalian cell lines. Methods 2014; 69: 151-70.Bernstein D.L., Le Lay J.E., Ruano E.G., Kaestner K.H. TALE-mediated epigenetic suppression of CDKN2A increases replication in human fibroblasts. J. Clin. Invest. 2015; 125: 1998-2006.Maeder M.L., Angstman J.F., Richardson M.E. et al. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nat. Biotechnol. 2013; 31: 1137-42.Chen H., Kazemier H.G., de Groote M.L. et al. Induced DNA demethylation by targeting Ten-Eleven Translocation 2 to the human ICAM-1 promoter. Nucleic Acids Res. 2014; 42: 1563-74.Gregory D.J., Zhang Y., Kobzik L., Fedulov A.V. Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation. Epigenetics 2013; 8: 1205-12.Gregory D.J., Mikhaylova L., Fedulov A.V. Selective DNA demethylation by fusion of TDG with a sequence-specific DNA-binding domain. Epigenetics 2012; 7: 344-9.Cortazar D., Kunz C., Saito Y. et al. The enigmatic thymine DNA glycosylase. DNA Repair 2007; 6: 489-504.Yaung S.J., Esvelt K.M., Church G.M. CRISPR/Cas9-mediated phage resistance is not impeded by the DNA modifications of phage T4. PLoS ONE. 2014; 9: e98811.Li F., Papworth M., Minczuk M., Rohde C., Zhang Y., Ragozin S., Jeltsch A. Chimeric DNA methyltransferases target DNA methylation to specific DNA sequences and repress expression of target genes. Nucleic Acids Res. 2007; 35: 100-12.Hsu C.-C., Li H.-P., Hung Y.-H. et al. Targeted methylation of CMV and E1A viral promoters. Biochem. Biophys. Res. Commun. 2010; 402: 228-34.Law J.A., Jacobsen S.E. Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 2010; 11: 204-20.