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• W3127860302 abstract "The germ cell lineage gives rise to totipotency and perpetuates and diversifies genetic as well as epigenetic information. Specifically, germ cells undergo epigenetic reprogramming/programming, replicate genetic information with high fidelity, and create genetic diversity through meiotic recombination. Driven by advances in our understanding of the mechanisms underlying germ cell development and stem cell/reproductive technologies, research over the past 2 decades has culminated in the in vitro reconstitution of mammalian germ cell development: mouse pluripotent stem cells (PSCs) can now be induced into primordial germ cell-like cells (PGCLCs) and then differentiated into fully functional oocytes and spermatogonia, and human PSCs can be induced into PGCLCs and into early oocytes and prospermatogonia with epigenetic reprogramming. Here, I provide my perspective on the key investigations that have led to the in vitro reconstitution of mammalian germ cell development, which will be instrumental in exploring salient themes in germ cell biology and, with further refinements/extensions, in developing innovative medical applications. The germ cell lineage gives rise to totipotency and perpetuates and diversifies genetic as well as epigenetic information. Specifically, germ cells undergo epigenetic reprogramming/programming, replicate genetic information with high fidelity, and create genetic diversity through meiotic recombination. Driven by advances in our understanding of the mechanisms underlying germ cell development and stem cell/reproductive technologies, research over the past 2 decades has culminated in the in vitro reconstitution of mammalian germ cell development: mouse pluripotent stem cells (PSCs) can now be induced into primordial germ cell-like cells (PGCLCs) and then differentiated into fully functional oocytes and spermatogonia, and human PSCs can be induced into PGCLCs and into early oocytes and prospermatogonia with epigenetic reprogramming. Here, I provide my perspective on the key investigations that have led to the in vitro reconstitution of mammalian germ cell development, which will be instrumental in exploring salient themes in germ cell biology and, with further refinements/extensions, in developing innovative medical applications. Germ cells are a source of totipotency and an enduring link between generations, ensuring the transmission of genetic as well as epigenetic information to successive generations. This contrasts with somatic cells, which die away after differentiation and contribution to organismal physiology. The dichotomy between germ cells and somatic cells has naturally led to an assumption that germ cells bear key regulatory mechanisms that realize their unique and fundamental functions, and seminal experiments have created a conceptual framework explaining the basis for such capacities. In an early and prominent example, somatic cell nuclear transfer into oocytes in frogs revealed the remarkable capacity of oocytes to reprogram the somatic cell nucleus into totipotency and, at the same time, demonstrated that genetic information itself is preserved in somatic cells during organismal development (Gurdon, 1962Gurdon J.B. Adult frogs derived from the nuclei of single somatic cells.Dev. Biol. 1962; 4: 256-273Crossref PubMed Google Scholar). Two decades later, parental pronuclear transplantation experiments in mice established the concept of genome imprinting and predicted the reprogramming of imprinting during germ cell development (McGrath and Solter, 1984McGrath J. Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes.Cell. 1984; 37: 179-183Abstract Full Text PDF PubMed Scopus (1057) Google Scholar; Surani et al., 1984Surani M.A. Barton S.C. Norris M.L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis.Nature. 1984; 308: 548-550Crossref PubMed Google Scholar). These works, together with the measurement of DNA methylation dynamics during germ cell development, which suggested that germ cells erase and re-establish genome-wide DNA methylation during their development (Monk et al., 1987Monk M. Boubelik M. Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development.Development. 1987; 99: 371-382Crossref PubMed Google Scholar), provided some of the first evidence that germ cells undergo “epigenetic reprogramming.” Meanwhile, genetic experiments revealed that germ cells exhibit an enhanced genetic integrity and a significantly lower frequency of spontaneous mutations compared with somatic cells (Ehling and Neuhauser, 1979Ehling U.H. Neuhauser A. Procarbazine-induced specific-locus mutations in male mice.Mutat. Res. 1979; 59: 245-256Crossref PubMed Google Scholar; Murphey et al., 2013Murphey P. McLean D.J. McMahan C.A. Walter C.A. McCarrey J.R. Enhanced genetic integrity in mouse germ cells.Biol. Reprod. 2013; 88: 6Crossref PubMed Scopus (28) Google Scholar; Russell et al., 1979Russell L.B. Russell W.L. Kelly E.M. Analysis of the albino-locus region of the mouse. I. Origin and viability.Genetics. 1979; 91: 127-139PubMed Google Scholar). On the other hand, it has been well established that germ cells are the only cells that are programmed to undergo meiotic recombination of parental chromosomes and generate sexually dimorphic gametes bearing a haploid genome for fertilization, thereby giving rise to enormous genetic diversity (Baudat et al., 2013Baudat F. Imai Y. de Massy B. Meiotic recombination in mammals: localization and regulation.Nat. Rev. Genet. 2013; 14: 794-806Crossref PubMed Scopus (285) Google Scholar). Thus, to fulfill their salient functions, germ cells acquire at least three key capacities during their development: the capacity to reprogram epigenetic information into totipotency, the capacity to preserve genetic information with high fidelity, and the capacity to create genetic diversity through meiotic recombination and fertilization. Nonetheless, until relatively recently, little has been known regarding the molecular mechanisms that underpin these key functions in germ cells, particularly in mammals. One approach to elucidating the mechanisms underlying the capacities of germ cells would be to understand the mechanism and the consequences of germ cell specification. Two distinct modes have been identified for germ cell specification in metazoans: one is “epigenesis,” which involves the induction of germ cell fate in pluripotent precursors, and the other is “preformation,” in which blastomeres that inherit a preformed “germplasm” in oocytes take on the germ cell fate (Extavour and Akam, 2003Extavour C.G. Akam M. Mechanisms of germ cell specification across the metazoans: epigenesis and preformation.Development. 2003; 130: 5869-5884Crossref PubMed Scopus (508) Google Scholar). The former appears to be evolutionarily ancestral and is seen in organisms including mammals, whereas the latter has expanded by convergent evolution and is seen in many model organisms such as C. elegans, D. melanogaster, Danio rerio, and X. laevis. By the early 2000s, the mechanism for the latter had been relatively well investigated using genetics approaches in D. melanogaster and C. elegans, leading to the identification of key genes essential for their germ cell specification and to the concept that germ cell specification requires a transcriptional silencing imposed by the germplasm components (Seydoux and Strome, 1999Seydoux G. Strome S. Launching the germline in Caenorhabditis elegans: regulation of gene expression in early germ cells.Development. 1999; 126: 3275-3283Crossref PubMed Google Scholar). In contrast, the mechanism for the former, though clearly distinct from preformation, was largely unclear at the start of the millennium, and its elucidation was a key challenge. On the other hand, histological studies revealed that, in mice, primordial germ cells (mouse PGCs: mPGCs), the founders of the germ cell lineage, become discernable as alkaline phosphatase-positive cells at around embryonic day (E) 7.25 at the base of the incipient allantois in the extraembryonic mesoderm (Chiquoine, 1954Chiquoine A.D. The identification, origin and migration of the primordial germ cells in the mouse embryo.Anat. Rec. 1954; 118: 135-146Crossref PubMed Google Scholar; Ginsburg et al., 1990Ginsburg M. Snow M.H. McLaren A. Primordial germ cells in the mouse embryo during gastrulation.Development. 1990; 110: 521-528Crossref PubMed Google Scholar). Pioneering clonal analyses indicated that the mPGC precursors reside within the epiblast cells most proximal to the extraembryonic ectoderm at E6.0; at E6.5 these precursors move posteriorly, and at around E7.25, the mPGCs are lineage restricted from their close somatic relatives, including the allantoic mesoderm cells (Lawson and Hage, 1994Lawson K.A. Hage W.J. Clonal analysis of the origin of primordial germ cells in the mouse.Ciba Found. Symp. 1994; 182: 68-84PubMed Google Scholar). Remarkably, analyses of embryos deficient for bone morphogenetic protein 4 (BMP4), which shows a specific expression in the extraembryonic ectoderm from around E5.5, revealed that BMP4 is an essential signal for mPGC specification (Lawson et al., 1999Lawson K.A. Dunn N.R. Roelen B.A. Zeinstra L.M. Davis A.M. Wright C.V. Korving J.P. Hogan B.L. Bmp4 is required for the generation of primordial germ cells in the mouse embryo.Genes Dev. 1999; 13: 424-436Crossref PubMed Google Scholar). Because not only mPGCs but also their somatic relatives, including the allantois, are absent in BMP4-deficient embryos, it was suggested that BMP4 may play a dose-dependent function in the lineage specification of mPGCs and their somatic relatives, or there may exist an additional signal that specifically determines the germ cell fate (two-signal model) (Lawson et al., 1999Lawson K.A. Dunn N.R. Roelen B.A. Zeinstra L.M. Davis A.M. Wright C.V. Korving J.P. Hogan B.L. Bmp4 is required for the generation of primordial germ cells in the mouse embryo.Genes Dev. 1999; 13: 424-436Crossref PubMed Google Scholar; McLaren, 1999McLaren A. Signaling for germ cells.Genes Dev. 1999; 13: 373-376Crossref PubMed Google Scholar). Building on this foundation, single-cell cDNA differential screening between putative mPGCs and their somatic neighbors defined by the expression of several marker genes was performed, and this screening identified genes specifically or highly expressed in mPGCs, including Stella/Dppa3, Fragilis/Ifitm3, Blimp1/Prdm1, and Prdm14, creating the basis for a systematic analysis of the mechanism of mPGC specification (Ohinata et al., 2005Ohinata Y. Payer B. O'Carroll D. Ancelin K. Ono Y. Sano M. Barton S.C. Obukhanych T. Nussenzweig M. Tarakhovsky A. et al.Blimp1 is a critical determinant of the germ cell lineage in mice.Nature. 2005; 436: 207-213Crossref PubMed Scopus (699) Google Scholar; Saitou et al., 2002Saitou M. Barton S.C. Surani M.A. A molecular programme for the specification of germ cell fate in mice.Nature. 2002; 418: 293-300Crossref PubMed Scopus (663) Google Scholar; Yamaji et al., 2008Yamaji M. Seki Y. Kurimoto K. Yabuta Y. Yuasa M. Shigeta M. Yamanaka K. Ohinata Y. Saitou M. Critical function of Prdm14 for the establishment of the germ cell lineage in mice.Nat. Genet. 2008; 40: 1016-1022Crossref PubMed Scopus (375) Google Scholar). Notably, it was shown that Blimp1 begins to be expressed in the most proximal epiblast cells from around E6.25, Blimp1-expressing cells contribute specifically to mPGCs, and Blimp1 is essential for mPGC specification, but not for specification of the somatic neighbors, including the allantois, unequivocally defining the origin of the germ cell lineage in mice (Ohinata et al., 2005Ohinata Y. Payer B. O'Carroll D. Ancelin K. Ono Y. Sano M. Barton S.C. Obukhanych T. Nussenzweig M. Tarakhovsky A. et al.Blimp1 is a critical determinant of the germ cell lineage in mice.Nature. 2005; 436: 207-213Crossref PubMed Scopus (699) Google Scholar). Blimp1 was shown to function as a master regulator for the terminal differentiation of B cells into plasma cells by “extinguishing” the B cell gene-expression program (Keller and Maniatis, 1991Keller A.D. Maniatis T. Identification and characterization of a novel repressor of beta-interferon gene expression.Genes Dev. 1991; 5: 868-879Crossref PubMed Google Scholar; Shaffer et al., 2002Shaffer A.L. Lin K.I. Kuo T.C. Yu X. Hurt E.M. Rosenwald A. Giltnane J.M. Yang L. Zhao H. Calame K. et al.Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program.Immunity. 2002; 17: 51-62Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar; Shapiro-Shelef et al., 2003Shapiro-Shelef M. Lin K.I. McHeyzer-Williams L.J. Liao J. McHeyzer-Williams M.G. Calame K. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells.Immunity. 2003; 19: 607-620Abstract Full Text Full Text PDF PubMed Scopus (568) Google Scholar). The finding that a master regulator for somatic cell terminal differentiation also specifies the germ cell fate was surprising, and the known function of BLIMP1 as a robust transcriptional repressor was reminiscent of transcriptional silencing for germ cell specification in D. melanogaster and C. elegans (Nakamura and Seydoux, 2008Nakamura A. Seydoux G. Less is more: specification of the germline by transcriptional repression.Development. 2008; 135: 3817-3827Crossref PubMed Scopus (74) Google Scholar; Seydoux and Strome, 1999Seydoux G. Strome S. Launching the germline in Caenorhabditis elegans: regulation of gene expression in early germ cells.Development. 1999; 126: 3275-3283Crossref PubMed Google Scholar). Subsequently, the original single-cell cDNA amplification method was improved for quantitative single-cell cDNA microarray analyses (Kurimoto et al., 2006Kurimoto K. Yabuta Y. Ohinata Y. Ono Y. Uno K.D. Yamada R.G. Ueda H.R. Saitou M. An improved single-cell cDNA amplification method for efficient high-density oligonucleotide microarray analysis.Nucleic Acids Res. 2006; 34: e42Crossref PubMed Scopus (287) Google Scholar), which were applied to the exploration of global gene-expression dynamics during mPGC specification, revealing that mPGC specification consists of at least three key events, i.e., repression of the somatic program, reacquisition of the pluripotency network, and ensuing epigenetic reprogramming (Kurimoto et al., 2008Kurimoto K. Yabuta Y. Ohinata Y. Shigeta M. Yamanaka K. Saitou M. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice.Genes Dev. 2008; 22: 1617-1635Crossref PubMed Scopus (246) Google Scholar) (see below), and that Blimp1 is essential for all three events and Prdm14 for at least the last two (Kurimoto et al., 2008Kurimoto K. Yabuta Y. Ohinata Y. Shigeta M. Yamanaka K. Saitou M. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice.Genes Dev. 2008; 22: 1617-1635Crossref PubMed Scopus (246) Google Scholar; Yamaji et al., 2008Yamaji M. Seki Y. Kurimoto K. Yabuta Y. Yuasa M. Shigeta M. Yamanaka K. Ohinata Y. Saitou M. Critical function of Prdm14 for the establishment of the germ cell lineage in mice.Nat. Genet. 2008; 40: 1016-1022Crossref PubMed Scopus (375) Google Scholar). The single-cell cDNA microarray procedure was later extended into the first single-cell RNA sequence technology (Tang et al., 2009Tang F. Barbacioru C. Wang Y. Nordman E. Lee C. Xu N. Wang X. Bodeau J. Tuch B.B. Siddiqui A. et al.mRNA-Seq whole-transcriptome analysis of a single cell.Nat. Methods. 2009; 6: 377-382Crossref PubMed Scopus (1270) Google Scholar). The identification of Blimp1 as a gene that defines the origin of the germ cell lineage promoted understanding of the signaling mechanism for germ cell specification. Accordingly, it was shown that essentially all the epiblast cells from ∼E5.75 to ∼E6.25, but not those from earlier or later, are competent to generate mPGCs in response to BMP4 in a dose-dependent manner, and in developing embryos, the allocation of the germ cell fate is constrained by the balance between the inducing, i.e., BMP4, and the antagonizing signals that the epiblast cells receive from surrounding extraembryonic tissues (Ohinata et al., 2009Ohinata Y. Ohta H. Shigeta M. Yamanaka K. Wakayama T. Saitou M. A signaling principle for the specification of the germ cell lineage in mice.Cell. 2009; 137: 571-584Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). Importantly, as originally demonstrated for mPGCs in vivo (Chuma et al., 2005Chuma S. Kanatsu-Shinohara M. Inoue K. Ogonuki N. Miki H. Toyokuni S. Hosokawa M. Nakatsuji N. Ogura A. Shinohara T. Spermatogenesis from epiblast and primordial germ cells following transplantation into postnatal mouse testis.Development. 2005; 132: 117-122Crossref PubMed Scopus (95) Google Scholar), PGCs induced from the epiblast by BMP4 ex vivo contributed to spermatogenesis upon transplantation into testes of neonatal mice, demonstrating their functional potential as bone fide germ cells (Ohinata et al., 2009Ohinata Y. Ohta H. Shigeta M. Yamanaka K. Wakayama T. Saitou M. A signaling principle for the specification of the germ cell lineage in mice.Cell. 2009; 137: 571-584Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). Thus, a basic framework for elucidating the mechanism for germ cell specification in mice at the signaling and transcriptional levels was established. Until the 1990s, the major epigenetic modifications known to play key roles in gene regulation were DNA methylation (Li et al., 1992Li E. Bestor T.H. Jaenisch R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality.Cell. 1992; 69: 915-926Abstract Full Text PDF PubMed Scopus (3033) Google Scholar) and histone acetylation (Brownell et al., 1996Brownell J.E. Zhou J. Ranalli T. Kobayashi R. Edmondson D.G. Roth S.Y. Allis C.D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation.Cell. 1996; 84: 843-851Abstract Full Text Full Text PDF PubMed Scopus (1210) Google Scholar). In the early 2000s, there was dramatic progress in our understanding of the epigenetic regulation of gene expression, with the identification and functional characterization of histone methyltransferases bearing the SET (Suv39/Enhancer of zeste/Trithorax) domains and the proposition of the histone code hypothesis for gene expression/cellular identity and memory, which was based on the relatively stable nature of methylation compared with other modifications, such as acetylation and phosphorylation (Jenuwein and Allis, 2001Jenuwein T. Allis C.D. Translating the histone code.Science. 2001; 293: 1074-1080Crossref PubMed Scopus (7073) Google Scholar; Rea et al., 2000Rea S. Eisenhaber F. O'Carroll D. Strahl B.D. Sun Z.W. Schmid M. Opravil S. Mechtler K. Ponting C.P. Allis C.D. et al.Regulation of chromatin structure by site-specific histone H3 methyltransferases.Nature. 2000; 406: 593-599Crossref PubMed Scopus (2005) Google Scholar). The enzymes for histone demethylases and DNA demethylases (see below) were subsequently identified (Shi et al., 2004Shi Y. Lan F. Matson C. Mulligan P. Whetstine J.R. Cole P.A. Casero R.A. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1.Cell. 2004; 119: 941-953Abstract Full Text Full Text PDF PubMed Scopus (2764) Google Scholar; Tahiliani et al., 2009Tahiliani M. Koh K.P. Shen Y. Pastor W.A. Bandukwala H. Brudno Y. Agarwal S. Iyer L.M. Liu D.R. Aravind L. et al.Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.Science. 2009; 324: 930-935Crossref PubMed Scopus (3643) Google Scholar), creating a basis for investigating the epigenetic regulation at a systems level (Klose et al., 2006Klose R.J. Kallin E.M. Zhang Y. JmjC-domain-containing proteins and histone demethylation.Nat. Rev. Genet. 2006; 7: 715-727Crossref PubMed Scopus (848) Google Scholar; Wu and Zhang, 2014Wu H. Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions.Cell. 2014; 156: 45-68Abstract Full Text Full Text PDF PubMed Scopus (632) Google Scholar). On the other hand, it was a surprising discovery that the epigenetic states of somatic cells are reprogrammed to an embryonic pluripotent state through the expression of only a few defined factors to generate induced pluripotent stem cells (iPSCs) in both mice and humans (Takahashi et al., 2007Takahashi K. Tanabe K. Ohnuki M. Narita M. Ichisaka T. Tomoda K. Yamanaka S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors.Cell. 2007; 131: 861-872Abstract Full Text Full Text PDF PubMed Scopus (13015) Google Scholar; Takahashi and Yamanaka, 2006Takahashi K. Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.Cell. 2006; 126: 663-676Abstract Full Text Full Text PDF PubMed Scopus (16400) Google Scholar). It is also of note that the first draft of the human genome sequence was completed in early 2000 (Lander et al., 2001Lander E.S. Linton L.M. Birren B. Nusbaum C. Zody M.C. Baldwin J. Devon K. Dewar K. Doyle M. FitzHugh W. et al.Initial sequencing and analysis of the human genome.Nature. 2001; 409: 860-921Crossref PubMed Scopus (16107) Google Scholar), and those of many other key organisms, including mice, followed soon thereafter (Waterston et al., 2002Waterston R.H. Lindblad-Toh K. Birney E. Rogers J. Abril J.F. Agarwal P. Agarwala R. Ainscough R. Alexandersson M. An P. et al.Initial sequencing and comparative analysis of the mouse genome.Nature. 2002; 420: 520-562Crossref PubMed Scopus (4935) Google Scholar), accelerating the discovery of genes with key functions and the establishment of genome-wide analysis technologies/platforms, including RNA sequencing (Wang et al., 2009Wang Z. Gerstein M. Snyder M. RNA-Seq: a revolutionary tool for transcriptomics.Nat. Rev. Genet. 2009; 10: 57-63Crossref PubMed Scopus (7081) Google Scholar), chromatin immunoprecipitation sequencing (Barski et al., 2007Barski A. Cuddapah S. Cui K. Roh T.Y. Schones D.E. Wang Z. Wei G. Chepelev I. Zhao K. High-resolution profiling of histone methylations in the human genome.Cell. 2007; 129: 823-837Abstract Full Text Full Text PDF PubMed Scopus (4567) Google Scholar; Johnson et al., 2007Johnson D.S. Mortazavi A. Myers R.M. Wold B. Genome-wide mapping of in vivo protein-DNA interactions.Science. 2007; 316: 1497-1502Crossref PubMed Scopus (1782) Google Scholar; Mikkelsen et al., 2007Mikkelsen T.S. Ku M. Jaffe D.B. Issac B. Lieberman E. Giannoukos G. Alvarez P. Brockman W. Kim T.K. Koche R.P. et al.Genome-wide maps of chromatin state in pluripotent and lineage-committed cells.Nature. 2007; 448: 553-560Crossref PubMed Scopus (2981) Google Scholar; Robertson et al., 2007Robertson G. Hirst M. Bainbridge M. Bilenky M. Zhao Y. Zeng T. Euskirchen G. Bernier B. Varhol R. Delaney A. et al.Genome-wide profiles of STAT1 DNA association using chromatin immunoprecipitation and massively parallel sequencing.Nat. Methods. 2007; 4: 651-657Crossref PubMed Scopus (976) Google Scholar), and whole-genome bisulfite sequencing (WGBS) (Cokus et al., 2008Cokus S.J. Feng S. Zhang X. Chen Z. Merriman B. Haudenschild C.D. Pradhan S. Nelson S.F. Pellegrini M. Jacobsen S.E. Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning.Nature. 2008; 452: 215-219Crossref PubMed Scopus (1470) Google Scholar; Hayatsu and Shiragami, 1979Hayatsu H. Shiragami M. Reaction of bisulfite with the 5-hydroxymethyl group in pyrimidines and in phage DNAs.Biochemistry. 1979; 18: 632-637Crossref PubMed Google Scholar; Lister et al., 2008Lister R. O'Malley R.C. Tonti-Filippini J. Gregory B.D. Berry C.C. Millar A.H. Ecker J.R. Highly integrated single-base resolution maps of the epigenome in Arabidopsis.Cell. 2008; 133: 523-536Abstract Full Text Full Text PDF PubMed Scopus (1634) Google Scholar). Coincident with the above research, epigenetic dynamics during germ cell development in mice were also investigated using various technologies. Key findings in this line of investigation include the apparent significant upregulation of genome-wide histone H3 lysine 27 trimethylation (H3K27me3) levels and downregulation of H3K9me2 levels in germ cells that colonize embryonic gonads (oogonia/gonocytes) (at ∼E12.5) (Seki et al., 2005Seki Y. Hayashi K. Itoh K. Mizugaki M. Saitou M. Matsui Y. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice.Dev. Biol. 2005; 278: 440-458Crossref PubMed Scopus (368) Google Scholar, Seki et al., 2007Seki Y. Yamaji M. Yabuta Y. Sano M. Shigeta M. Matsui Y. Saga Y. Tachibana M. Shinkai Y. Saitou M. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice.Development. 2007; 134: 2627-2638Crossref PubMed Scopus (297) Google Scholar). Most notably, consistent with classical studies involving Southern blot analysis and more locus-specific analyses such as those analyzing imprint genes (Hajkova et al., 2002Hajkova P. Erhardt S. Lane N. Haaf T. El-Maarri O. Reik W. Walter J. Surani M.A. Epigenetic reprogramming in mouse primordial germ cells.Mech. Dev. 2002; 117: 15-23Crossref PubMed Scopus (909) Google Scholar; Kafri et al., 1992Kafri T. Ariel M. Brandeis M. Shemer R. Urven L. McCarrey J. Cedar H. Razin A. Developmental pattern of gene-specific DNA methylation in the mouse embryo and germ line.Genes Dev. 1992; 6: 705-714Crossref PubMed Google Scholar; Monk et al., 1987Monk M. Boubelik M. Lehnert S. Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development.Development. 1987; 99: 371-382Crossref PubMed Google Scholar), the WGBS analysis revealed that gonadal germ cells indeed erase nearly all DNA methylation in their genome, and unlike typical somatic cells and embryonic cells, including the epiblast cells that bear ∼80% of genome-wide CpG methylation (5mC) levels, gonadal germ cells show only ∼5% of 5mC and the remaining methylations are enriched in sequences such as evolutionary young endogenous retroviruses (Popp et al., 2010Popp C. Dean W. Feng S. Cokus S.J. Andrews S. Pellegrini M. Jacobsen S.E. Reik W. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.Nature. 2010; 463: 1101-1105Crossref PubMed Scopus (661) Google Scholar). These findings establish the concept that germ cells nearly completely erase their parental epigenetic memory based on DNA methylation relatively early during their development (during the mPGC stage) and perhaps reprogram genome-wide histone modifications so that they ensure the epigenetic integrity of the DNA methylation-free epigenome. The remaining DNA methylation can serve as a basis for transgenerational epigenetic inheritance (Lane et al., 2003Lane N. Dean W. Erhardt S. Hajkova P. Surani A. Walter J. Reik W. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse.Genesis. 2003; 35: 88-93Crossref PubMed Scopus (495) Google Scholar; Popp et al., 2010Popp C. Dean W. Feng S. Cokus S.J. Andrews S. Pellegrini M. Jacobsen S.E. Reik W. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.Nature. 2010; 463: 1101-1105Crossref PubMed Scopus (661) Google Scholar). The mechanism for the genome-wide DNA demethylation in germ cells has been a subject of intensive investigation, and two relevant mechanisms have been proposed: one is enzyme-based active DNA demethylation and the other is replication-coupled, passive DNA demethylation (Hajkova et al., 2002Hajkova P. Erhardt S. Lane N. Haaf T. El-Maarri O. Reik W. Walter J. Surani M.A. Epigenetic reprogramming in mouse primordial germ cells.Mech. Dev. 2002; 117: 15-23Crossref PubMed Scopus (909) Google Scholar). The identification of DNA demethylases, first in plants (DEMETER: DNA glycosylase) (Gehring et al., 2006Gehring M. Huh J.H. Hsieh T.F. Penterman J. Choi Y. Harada J.J. Goldberg R.B. Fischer R.L. DEMETER DNA glycosylase establishes MEDEA polycomb gene self-imprinting by allele-specific demethylation.Cell. 2006; 124: 495-506Abstract Full Text Full Text PDF PubMed Scopus (474) Google Scholar) and then in mammals (TET1/2/3 [Ten-eleven translocation]: 5mC dioxygenase that converts 5mC into 5-hydroxymethylcytosine [5hmC]) (Tahiliani et al., 2009Tahiliani M. Koh K.P. Shen Y. Pastor W.A. Bandukwala H. Brudno Y. Agarwal S. Iyer L.M. Liu D.R. Aravind L. et al.Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1.Science. 2009; 324: 930-935Crossref PubMed Scopus (3643) Google Scholar), was an exciting advance, and many investigations have since been performed to explore the role of TET enzymes in physiological contexts (Saitou et al., 2012Saitou M. Kagiwada S. Kurimoto K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells.Development. 2012; 139: 15-31Crossref PubMed Scopus (261) Google Scholar; Wu and Zhang, 2014Wu H. Zhang Y. Reversing DNA methylation: mechanisms, genomics, and biological functions.Cell. 2014; 156: 45-68Abstract Full Text Full Text PDF PubMed Scopus (632) Google Scholar). A key conclusion, however, has been that although TET enzymes indeed play pivotal roles in gene regulation by binding to CpG-rich promoters through their CXXC motifs and regulating their DNA methylation fidelity in various contexts (Saitou et al., 2012Saitou M. Kagiwada S. Kurimoto K. Epigenetic reprogramming in mouse pre-implantation developme" @default.
• W3127860302 created "2021-02-15" @default.
• W3127860302 creator A5000648036 @default.
• W3127860302 date "2021-04-01" @default.
• W3127860302 modified "2023-10-17" @default.
• W3127860302 title "Mammalian Germ Cell Development: From Mechanism to In Vitro Reconstitution" @default.
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