DNA甲基化在哺乳动物卵母细胞和早期胚胎发育中的研究进展

doi:10.11843/j.issn.0366-6964.2023.02.003

摘要/Abstract

摘要： DNA甲基化（DNA methylation）是一种动态、可逆并可以遗传的表观遗传修饰模式，主要发生在哺乳动物原始生殖细胞和早期胚胎发育过程中，能够通过高动态和协同的核酶网络附着在DNA的CpG区域，同时还通过改变调控区域的功能状态进而调控基因表达且不影响DNA序列所携带的遗传信息。DNA甲基化主要涉及基因组印迹、转座元件沉默、X染色体失活和衰老等多种关键生理过程，在哺乳动物卵母细胞和胚胎发育中发挥着重要作用。本文介绍了DNA甲基化的建立与去除机制及其生物学功能，重点阐述了DNA甲基化在哺乳动物卵母细胞和胚胎发育过程中精准生成、维持、读取和删除等动态变化过程，为进一步研究哺乳动物表观遗传调控提供参考依据。

关键词: DNA甲基化, 卵母细胞, 胚胎发育, 表观遗传

Abstract: DNA methylation is a dynamic, reversible and heritable epigenetic modification pattern that mainly occurs in mammalian primordial germ cells and early embryonic development. DNA methylation can attach to the CpG region of DNA through highly dynamic and cooperative ribozyme networks, and it can also regulate gene expression by altering functional state of the regulatory regions without affecting genetic information carried by the DNA sequence. DNA methylation is mainly involved in a variety of key physiological processes such as genomic imprinting, transposable element silencing, X-chromosome inactivation and senescence, and plays an important role in mammalian oocyte and embryo development. This review introduces the establishment and removal mechanism of DNA methylation and the biological functions, with emphasis on the dynamic processes of precise generation, maintenance, reading and deletion of DNA methylation during mammalian oocyte and embryo development, providing basis for further studies on mammalian epigenetic regulation.

Key words: DNA methylation, oocyte, embryonic development, epigenetics

中图分类号:

S813.1

杨小耿, 张慧珠, 李键, 向华, 何翃闳. DNA甲基化在哺乳动物卵母细胞和早期胚胎发育中的研究进展[J]. 畜牧兽医学报, 2023, 54(2): 443-450.

YANG Xiaogeng, ZHANG Huizhu, LI Jian, XIANG Hua, HE Honghong. Research Progress of the DNA Methylation in Mammalian Oocyte and Early Embryo Development[J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(2): 443-450.

参考文献 75

[1]	BERNSTEIN B E, MEISSNER A, LANDER E S.The mammalian epigenome[J].Cell, 2007, 128(4):669-681.
[2]	DELCUVE G P, RASTEGAR M, DAVIE J R.Epigenetic control[J].J Cell Physiol, 2009, 219(2):243-250.
[3]	甘麦邻, 杨大洪, 谭娅, 等.环境因素引起的哺乳动物跨代DNA甲基化修饰现象[J].畜牧兽医学报, 2017, 48(12):2225-2231.GAN M L, YANG D H, TAN Y, et al.The study of influence of environment on transgenerational inheritance of DNA methylation in mammals[J].Acta Veterinaria et Zootechnica Sinica, 2017, 48(12):2225-2231.(in Chinese)
[4]	NISHIYAMA A, NAKANISHI M.Navigating the DNA methylation landscape of cancer[J].Trends Genet, 2021, 37(11):1012-1027.
[5]	HALUŠKOVA J, HOLEČKOVÁ B, STANIČOVÁ J.DNA methylation studies in cattle[J].J Appl Genet, 2021, 62(1):121-136.
[6]	XIE S, QIAN C M.The growing complexity of UHRF1-Mediated maintenance DNA methylation[J].Genes (Basel), 2018, 9(12):600.
[7]	SCHVBELER D.Function and information content of DNA methylation[J].Nature, 2015, 517(7534):321-326.
[8]	REN H L, TAYLOR R B, DOWNING T L, et al.Locally correlated kinetics of post-replication DNA methylation reveals processivity and region specificity in DNA methylation maintenance[J].J Roy Soc Interface, 2022, 19(195):20220415.
[9]	MING X, ZHANG Z Q, ZOU Z N, et al.Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration[J].Cell Res, 2020, 30(11):980-996.
[10]	GUO H S, ZHU P, YAN L Y, et al.The DNA methylation landscape of human early embryos[J].Nature, 2014, 511(7511):606-610.
[11]	SMITH Z D, CHAN M M, MIKKELSEN T S, et al.A unique regulatory phase of DNA methylation in the early mammalian embryo[J].Nature, 2012, 484(7394):339-344.
[12]	UYAL F, CINAR O, CAN A.Knockdown of Dnmt1 and Dnmt3a gene expression disrupts preimplantation embryo development through global DNA methylation[J].J Assist Reprod Genet, 2021, 38(12):3135-3144.
[13]	ZHOU X F, HE Y T, LI N, et al.DNA methylation mediated RSPO2 to promote follicular development in mammals[J].Cell Death Dis, 2021, 12(7):653.
[14]	MAUNAKEA A K, NAGARAJAN R P, BILENKY M, et al.Conserved role of intragenic DNA methylation in regulating alternative promoters[J].Nature, 2010, 466(7303):253-257.
[15]	SENDŽIKAIT[AKE·] G, KELSEY G.The role and mechanisms of DNA methylation in the oocyte[J].Essays Biochem, 2019, 63(6):691-705.
[16]	ZHANG J, HAO L L, WEI Q, et al.TET3 overexpression facilitates DNA reprogramming and early development of bovine SCNT embryos[J].Reproduction, 2020:160(3) 379-391.
[17]	NISHIYAMA A, MULHOLLAND C B, BULTMANN S, et al.Two distinct modes of DNMT1 recruitment ensure stable maintenance DNA methylation[J].Nat Commun, 2020, 11(1):1222.
[18]	PETRYK N, BULTMANN S, BARTKE T, et al.Staying true to yourself:mechanisms of DNA methylation maintenance in mammals[J].Nucl Acids Res, 2021, 49(6):3020-3032.
[19]	MAENOHARA S, UNOKI M, TOH H, et al.Role of UHRF1 in de novo DNA methylation in oocytes and maintenance methylation in preimplantation embryos[J].PLoS Genet, 2017, 13(10):e1007042.
[20]	李秦.抗坏血酸在牦牛卵母细胞和体外受精胚胎DNA甲基化调控中的应用[D].兰州:甘肃农业大学, 2020.LI Q.Application of ascorbic acid in the regulation of DNA methylation in yak oocytes and IVF embryos[D].Lanzhou:Gansu Agricultural University, 2020.(in Chinese)
[21]	LYKO F.The DNA methyltransferase family:a versatile toolkit for epigenetic regulation[J].Nat Rev Genet, 2018, 19(2):81-92.
[22]	GOLL M G, KIRPEKAR F, MAGGERT K A, et al.Methylation of tRNAAsp by the DNA methyltransferase homolog Dnmt2[J].Science, 2006, 311(5759):395-398.
[23]	王倩倩.双加氧酶Tet对DNA甲基化修饰的影响及相关调控机制研究[D].北京:中国农业大学, 2018.WANG Q Q.Effects of Tet dioxygenases on DNA methylation and related regulatory mechanisms[D].Beijing:China Agricultural University, 2018.(in Chinese)
[24]	ITO T, KUBIURA-ICHIMARU M, MURAKAMI Y, et al.DNMT1 regulates the timing of DNA methylation by DNMT3 in an enzymatic activity-dependent manner in mouse embryonic stem cells[J].PLoS One, 2022, 17(1):e0262277.
[25]	CHEN Z Y, ZHANG Y.Role of mammalian DNA methyltransferases in development[J].Annu Rev Biochem, 2020, 89:135-158.
[26]	YAGI M, KABATA M, TANAKA A, et al.Identification of distinct loci for de novo DNA methylation by DNMT3A and DNMT3B during mammalian development[J].Nat Commun, 2020, 11(1):3199.
[27]	LI Y L, CHEN X, LU C.The interplay between DNA and histone methylation:molecular mechanisms and disease implications[J].EMBO Rep, 2021, 22(5):e51803.
[28]	BARAU J, TEISSANDIER A, ZAMUDIO N, et al.The DNA methyltransferase DNMT3C protects male germ cells from transposon activity[J].Science, 2016, 354(6314):909-912.
[29]	UYSAL F, AKKOYUNLU G, OZTURK S.Dynamic expression of DNA methyltransferases (DNMTs) in oocytes and early embryos[J].Biochimie, 2015, 116:103-113.
[30]	ZHAO X B, CHEN Y P, TAN M, et al.Extracellular matrix stiffness regulates DNA methylation by PKCα-dependent nuclear transport of DNMT3L[J].Adv Healthc Mater, 2021, 10(16):2100821.
[31]	TOMIZAWA S I, NOWACKA-WOSZUK J, KELSEY G.DNA methylation establishment during oocyte growth:mechanisms and significance[J].Int J Dev Biol, 2012, 56(10-12):867-875.
[32]	GREENBERG M V C.Get out and stay out:new insights into DNA methylation reprogramming in mammals[J].Front Cell Dev Biol, 2021, 8:629068.
[33]	WU X J, ZHANG Y.TET-mediated active DNA demethylation:mechanism, function and beyond[J].Nat Rev Genet, 2017, 18(9):517-534.
[34]	FICZ G, BRANCO M R, SEISENBERGER S, et al.Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation[J].Nature, 2011, 473(7347):398-402.
[35]	CAO J Z, LIU H, WICKREMA A, et al.HIF-1 directly induces TET3 expression to enhance 5-hmC density and induce erythroid gene expression in hypoxia[J].Blood Adv, 2020, 4(13):3053-3062.
[36]	MATULEVICIUTE R, CUNHA P P, JOHNSON R S, et al.Oxygen regulation of TET enzymes[J].FEBS J, 2021, 288(24):7143-7161.
[37]	GU T P, GUO F, YANG H, et al.The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes[J].Nature, 2011, 477(7366):606-610.
[38]	CHENG H, ZHANG J, ZHANG S, et al.Tet3 is required for normal in vitro fertilization preimplantation embryos development of bovine[J].Mol Reprod Dev, 2019, 86(3):298-307.
[39]	YAMAZAKI T, HATANO Y, TANIGUCHI R, et al.Editing DNA methylation in mammalian embryos[J].Int J Mol Sci, 2020, 21(2):637.
[40]	SAITOU M, KAGIWADA S, KURIMOTO K.Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells[J]. Development, 2012, 139(1):15-31.
[41]	BRANCO M R, ODA M, REIK W.Safeguarding parental identity:Dnmt1 maintains imprints during epigenetic reprogramming in early embryogenesis[J].Genes Dev, 2008, 22(12):1567-1571.
[42]	WU H, ZHANG Y.Reversing DNA methylation:mechanisms, genomics, and biological functions[J].Cell, 2014, 156(1-2):45-68.
[43]	SEISENBERGER S, PEAT J R, REIK W.Conceptual links between DNA methylation reprogramming in the early embryo and primordial germ cells[J].Curr Opin Cell Biol, 2013, 25(3):281-288.
[44]	YAKOVLEV A F.Epigenetic effects in livestock breeding[J].Russ J Genet, 2018, 54(8):897-909.
[45]	DE FELICI M.Nuclear reprogramming in mouse primordial germ cells:epigenetic contribution[J].Stem Cells Int, 2011, 2011:425863.
[46]	HIURA H, OBATA Y, KOMIYAMA J, et al.Oocyte growth-dependent progression of maternal imprinting in mice[J].Genes Cells, 2006, 11(4):353-361.
[47]	LUCIFERO D, MANN M R W, BARTOLOMEI M S, et al.Gene-specific timing and epigenetic memory in oocyte imprinting[J]. Hum Mol Genet, 2004, 13(8):839-849.
[48]	SWALES A K E, SPEARS N.Genomic imprinting and reproduction[J].Reproduction, 2005, 130(4):389-399.
[49]	SMALLWOOD S A, TOMIZAWA S I, KRUEGER F, et al.Dynamic CpG island methylation landscape in oocytes and preimplantation embryos[J].Nat Genet, 2011, 43(8):811-814.
[50]	SEISENBERGER S, ANDREWS S, KRUEGER F, et al.The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells[J].Mol Cell, 2012, 48(6):849-862.
[51]	UYSAL F, OZTURK S, AKKOYUNLU G.DNMT1, DNMT3A and DNMT3B proteins are differently expressed in mouse oocytes and early embryos[J].J Mol Histol, 2017, 48(5-6):417-426.
[52]	KOBAYASHI H, SAKURAI T, IMAI M, et al.Contribution of intragenic DNA methylation in mouse gametic DNA methylomes to establish oocyte-specific heritable marks[J].PLoS Genet, 2012, 8(1):e1002440.
[53]	OKAE H, CHIBA H, HIURA H, et al.Genome-wide analysis of DNA methylation dynamics during early human development[J]. PLoS Genet, 2014, 10(12):e1004868.
[54]	VESELOVSKA L, SMALLWOOD S A, SAADEH H, et al.Deep sequencing and de novo assembly of the mouse oocyte transcriptome define the contribution of transcription to the DNA methylation landscape[J].Genome Biol, 2015, 16:209.
[55]	SINGH V B, SRIBENJA S, WILSON K E, et al.Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome[J].Development, 2017, 144(10):1820-1830.
[56]	GREENBERG M V C, BOURC'HIS D.The diverse roles of DNA methylation in mammalian development and disease[J].Nat Rev Mol Cell Biol, 2019, 20(10):590-607.
[57]	RACEDO S E, WRENZYCKI C, LEPIKHOV K, et al.Epigenetic modifications and related mRNA expression during bovine oocyte in vitro maturation[J].Reprod Fertil Dev, 2009, 21(6):738-748.
[58]	LIANG Y, FU X W, LI J J, et al.DNA methylation pattern in mouse oocytes and their in vitro fertilized early embryos:effect of oocyte vitrification[J].Zygote, 2014, 22(2):138-145.
[59]	CANOVAS S, IVANOVA E, HAMDI M, et al.Culture medium and sex drive epigenetic reprogramming in preimplantation bovine embryos[J].Int J Mol Sci, 2021, 22(12):6426.
[60]	XU Q H, XIE W.Epigenome in early mammalian development:inheritance, reprogramming and establishment[J].Trends Cell Biol, 2018, 28(3):237-253.
[61]	WANG X G, BHANDARI R K.DNA methylation dynamics during epigenetic reprogramming of medaka embryo[J]. Epigenetics, 2019, 14(6):611-622.
[62]	SHEN L, INOUE A, HE J, et al.Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes[J].Cell Stem Cell, 2014, 15(4):459-471.
[63]	刘青青, 郑丽明, 刘红亮, 等.小鼠早期胚胎发育过程中的DNA去甲基化[J].畜牧兽医学报, 2013, 44(4):501-507.LIU Q Q, ZHENG L M, LIU H L, et al.DNA demethylation in mouse pre-implantation embryos[J].Acta Veterinaria et Zootechnica Sinica, 2013, 44(4):501-507.(in Chinese)
[64]	ZHU P, GUO H S, REN Y X, et al.Single-cell DNA methylome sequencing of human preimplantation embryos[J].Nat Genet, 2018, 50(1):12-19.
[65]	GUO F, LI X L, LIANG D, et al.Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote[J].Cell Stem Cell, 2014, 15(4):447-459.
[66]	ARAND J, REIJO PERA R A, WOSSIDLO M.Reprogramming of DNA methylation is linked to successful human preimplantation development[J].Histochem Cell Biol, 2021, 156(3):197-207.
[67]	IVANOVA E, CANOVAS S, GARCIA-MARTÍNEZ S, et al.DNA methylation changes during preimplantation development reveal inter-species differences and reprogramming events at imprinted genes[J].Clin Epigenet, 2020, 12(1):64.
[68]	甘建宇, 张芯, 蔡更元, 等.DNA甲基化在猪胚胎发育过程中的研究进展[J].畜牧兽医学报, 2022, 53(10):3287-3295.GAN J Y, ZHANG X, CAI G Y, et al.Research progress of DNA methylation during porcine embryonic development[J].Acta Veterinaria et Zootechnica Sinica, 2022, 53(10):3287-3295.(in Chinese)
[69]	XIONG X R, FU M, LAN D L, et al.Yak response to high-altitude hypoxic stress by altering mRNA expression and DNA methylation of hypoxia-inducible factors[J].Anim Biotechnol, 2015, 26(3):222-229.
[70]	KAPITSINOU P P, LIU Q D, UNGER T L, et al.Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia[J]. Blood, 2010, 116(16):3039-3048.
[71]	BENNEMANN J, GROTHMANN H, WRENZYCKI C.Reduced oxygen concentration during in vitro oocyte maturation alters global DNA methylation in the maternal pronucleus of subsequent zygotes in cattle[J].Mol Reprod Dev, 2018, 85(11):849-857.
[72]	CAO Y M, LI M R, LIU F, et al.Deletion of maternal UHRF1 severely reduces mouse oocyte quality and causes developmental defects in preimplantation embryos[J].FASEB J, 2019, 33(7):8294-8305.
[73]	BAKHTARI A, ROSS P J.DPPA3 prevents cytosine hydroxymethylation of the maternal pronucleus and is required for normal development in bovine embryos[J].Epigenetics, 2014, 9(9):1271-1279.
[74]	HAN L S, REN C, ZHANG J, et al.Differential roles of Stella in the modulation of DNA methylation during oocyte and zygotic development[J].Cell Discov, 2019, 5:9.
[75]	FUNAKI S, NAKAMURA T, NAKATANI T, et al.Inhibition of maintenance DNA methylation by Stella[J].Biochem Biophys Res Commun, 2014, 453(3):455-460.