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Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription

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Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription G C A T T A C G G C A T genes Review Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription Izabella Bajusz 1,*, Surya Henry 1,2, Enik˝oSutus 1,2, Gerg˝oKovács 1 and Melinda K. Pirity 1,* 1 Biological Research Centre, Temesvári krt. 62, H-6726 Szeged, Hungary; [email protected] (S.H.); [email protected] (E.S.); [email protected] (G.K.) 2 Doctoral School of Biology, Faculty of Science and Informatics University of Szeged, Dugonics tér 13, H-6720 Szeged, Hungary * Correspondence: [email protected] (I.B.); [email protected] (M.K.P.); Tel.: +36-62-599-520 (I.B.); +36-62-599-683 (M.K.P.) Received: 7 October 2019; Accepted: 14 November 2019; Published: 19 November 2019 Abstract: Separation of germline cells from somatic lineages is one of the earliest decisions of embryogenesis. Genes expressed in germline cells include apoptotic and meiotic factors, which are not transcribed in the soma normally, but a number of testis-specific genes are active in numerous cancer types. During germ cell development, germ-cell-specific genes can be regulated by specific transcription factors, retinoic acid signaling and multimeric protein complexes. Non-canonical polycomb repressive complexes, like ncPRC1.6, play a critical role in the regulation of the activity of germ-cell-specific genes. RING1 and YY1 binding protein (RYBP) is one of the core members of the ncPRC1.6. Surprisingly, the role of Rybp in germ cell differentiation has not been defined yet. This review is focusing on the possible role of Rybp in this process. By analyzing whole-genome transcriptome alterations of the Rybp-/- embryonic stem (ES) cells and correlating this data with experimentally identified binding sites of ncPRC1.6 subunits and retinoic acid receptors in ES cells, we propose a model how germ-cell-specific transcription can be governed by an RYBP centered regulatory network, underlining the possible role of RYBP in germ cell differentiation and tumorigenesis. Keywords: germ cell differentiation; transcriptional regulation; polycomb repression; Rybp; ncPRC1; Nanog; Oct4; Sall4; ubiquitylation; retinoic acid; apoptosis; meiosis; transcriptome 1. Introduction: Germline, Soma and Embryonic Stem Cells Differentiation of germ cells has crucial importance in the survival of species. Production of healthy germ cells is the basis of fertility. Our life starts with the fusion of the female and the male germ cells, which together form the totipotent zygote. The myriads of cells of our body with different sizes, morphologies, and functions develops from this unique cell, which not only contains all genetic information, but also has the potential to use it all. This is why germ cells are generally considered to be totipotent, “the stem cells of the species” [1,2]. Germinal linage is often considered as unipotent, since the only possible fate of the male germinal lineage is to produce sperm, if controlled by the testicular microenvironment. However, embryonic primordial germ cells (PGCs) and spermatogonial stem cells (SSCs) (Figure1) are able to change their fate and convert to pluripotent spontaneously in culture or during disease conditions like testicular carcinoma [3]. Germ cells express a series of pluripotency marker genes (e.g., Pou5f1/Oct4, Klf4, Nanog) and share certain characteristics of stem cells. As both pluripotency and germ cell marker genes are often upregulated in tumors [4] it is not surprising that germ cell fate determination attracts great attention. Genes 2019, 10, 941; doi:10.3390/genes10110941 www.mdpi.com/journal/genes Genes 2019, 10, 941 2 of 33 Genes 2019, 10, x FOR PEER REVIEW 2 of 33 Blastocyst γH2Ax Ddx4/Vasa Cd49f Dazl Cenp-a Plzf Sycp3 Sycp3 Fank1 PGCs Gonocytes SSCs Spermatocytes Ddx4/Vasa Ddx4/Vasa Dazl Dazl Ssea1/Fut4 cKit ES cells/ Ifitm3 Stella iPS cells cKit Prdm1a Stella Prdm14 Prdm1a Plzf Prdm14 Sycp3 Meiosis initiation Reprogramming PGCs Oogonia Primary oocytes Sycp3 γH2Ax Somatic cells Fank1 Figure 1. Schematic representation of differentiation pathways from ES/iPS cells into germ cells. Figure 1. Schematic representation of differentiation pathways from ES/iPS cells into germ cells. ES ES cells are derived from the mouse blastocyst, and iPS cells are reprogramed from adult somatic cells are derived from the mouse blastocyst, and iPS cells are reprogramed from adult somatic cells. cells. Both ES/iPS cells can be differentiated into PGCs and further towards either spermatocytes or Both ES/iPS cells can be differentiated into PGCs and further towards either spermatocytes or primary primary oocytes. Germ cell markers for the corresponding stages are marked as framed. Certain oocytes. Germ cell markers for the corresponding stages are marked as framed. Certain germ-cell- germ-cell-specific genes, like the ones coding for germ granule components like Ddx4/Vasa are active specific genes, like the ones coding for germ granule components like Ddx4/Vasa are active all through all through germ cell development, while others like Fank1 only expressed at distinctive phases of germ cell development, while others like Fank1 only expressed at distinctive phases of germ cell germ cell development. Abbreviations: ES: Embryonic stem, iPS: Induced pluripotent stem, PGCs: development. Abbreviations: ES: Embryonic stem, iPS: Induced pluripotent stem, PGCs: Primordial Primordial germ cells, SSCs: Spermatogonial stem cells. germ cells, SSCs: Spermatogonial stem cells. Gametogenesis has been thoroughly studied in model organisms, and in some aspects, in vitro differentiationGametogenesis systems has using been embryonic thoroughly stem studied (ES) in cells model [5, 6organisms,] and induced and in pluripotent some aspects, stem in (iPS) vitro cellsdifferentiation [7,8]. By now, systems a lot of using information embryonic has stem been (ES) gathered cells [5,6] about and the induced epigenetic pluripotent regulation, stem the (iPS) specific cells transcription[7,8]. By now, factors, a lot importantof information signalization has been events, gathered and about key e fftheectors epigenetic necessary regulation, for commitment the specific of stemtranscription cells to germline factors, fate important [9–14] from signalization different modelevents, organism and key andeffectors by in necessary vitro differentiation for commitment of stem of cellsstem to cells primordial to germline germ-cell-like fate [9–14] cells from (PGCLCs) different [9 –model17]. organism and by in vitro differentiation of stemGerm cells cellsto primordial profoundly germ-cell-like differ from somatic cells (PGCLCs) cells. They [9–17]. set apart during early embryogenesis and from thenGerm on, cells this profoundly separation isdiffer irreversible. from somatic Undi cells.fferentiated They set germ apart cells, during called early PGCs, embryogenesis are considered and tofrom be unipotent, then on, this they separation proceed onis irreversible. their own developmental Undifferentiated pathways germ cells, and called normally PGCs, give are rise considered to only moreto be matured unipotent, germ they cells proceed [18], mainly on their by own consecutive developmental mitotic divisions. pathways In and order normally to keep give the numberrise to only of chromosomesmore matured fixed germ when cells gametes [18], mainly of the by two consecutiv sexes fusee uponmitotic fertilization, divisions. PGCsIn order must to keep enter the meiosis number at certainof chromosomes points of their fixed development, when gametes before of completingthe two sexes gametogenesis. fuse upon fertilization, Meiosis is characteristic PGCs must onlyenter formeiosis germ cells,at certain and it neverpoints occurs of their in any development, somatic lineages. before During completing their development, gametogenesis. germ Meiosis cells go is throughcharacteristic a complex only epigenetic for germ reprogramming cells, and it processnever occurs [19], while in any at the somatic same time, lineages. imprinting During of theirtheir genomedevelopment, might enable germ cells the epigenetic go through inheritance a complex of epig certainenetic environmental reprogramming conditions process [[19],20–22 while]. at the sameCells time, of the imprinting soma follow of a completelytheir genome diff erentmight developmental enable the path.epigenetic As somatic inheritance cells di ffoferentiate certain fromenvironmental stem cells, during conditions embryonic [20–22]. development, these cells lose pluripotency, while their differentiation reachesCells terminal of the stages. soma The follow germ cella dicompletelyfferentiation different program developmental is closed for all somaticpath. As cells, somatic repression cells ofdifferentiate germ-cell-specific from stem and meiotic cells, during genes isembryonic continuously development, maintained these in the cells somatic lose lineage.pluripotency, Terminally while ditheirfferentiated differentiation somatic cellsreaches adopt terminal their distinctive stages. The morphology germ cell differentiation and function, and program this state is closed is normally for all somatic cells, repression of germ-cell-specific and meiotic genes is continuously maintained in the somatic lineage. Terminally differentiated somatic cells adopt their distinctive morphology and Genes 2019, 10, 941 3 of 33 irreversible. Pluripotency factors are not expressed in somatic cells and terminally differentiated somatic cells often enter G0 phase and stop dividing. Proliferating somatic cells divide only by mitosis. Their chromosome number remains the same,
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