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Review
. 2019 Nov 19;10(11):941.
doi: 10.3390/genes10110941.

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

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Free PMC article
Review

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

Izabella Bajusz et al. Genes (Basel). .
Free PMC article

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: Nanog; Oct4; Rybp; Sall4; apoptosis; germ cell differentiation; meiosis; ncPRC1; polycomb repression; retinoic acid; transcriptional regulation; transcriptome; ubiquitylation.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of differentiation pathways from ES/iPS cells into germ cells. ES cells are derived from the mouse blastocyst, and iPS cells are reprogramed from adult somatic cells. Both ES/iPS cells can be differentiated into PGCs and further towards either spermatocytes or primary oocytes. Germ cell markers for the corresponding stages are marked as framed. Certain germ-cell-specific genes, like the ones coding for germ granule components like Ddx4/Vasa are active all through germ cell development, while others like Fank1 only expressed at distinctive phases of germ cell development. Abbreviations: ES: Embryonic stem, iPS: Induced pluripotent stem, PGCs: Primordial germ cells, SSCs: Spermatogonial stem cells.
Figure 2
Figure 2
The non-canonical Polycomb Repressor Complex1.6 (ncPRC1.6) complex is targeted by DNA binding subunits and its core members co-exist only on a subset of targets. (A) Schematic representation of the ncPRC1.6 complex showing both activation [105] and repression activities [106]. (B) Venn diagram showing the common targets of Ring1 and YY1 binding protein (RYBP), Ring finger protein2 (RNF2/RING1B), and Polycomb group ring finger 6 (PCGF6). Chromatin Immune Precipitation followed by whole genome sequencing (ChIP-seq) raw data derived from Geo Database: ID GSM1041375 for RYBP, GSM1041372 for RING1B, and GSE84905 for PCGF6. List of the 65 common upregulated genes is found in Supplementary Materials S1.
Figure 3
Figure 3
RYBP regulates germ-cell-specific genes and is expressed in the adult mouse testis. (A) Common upregulated targets of Ring1 and YY1 binding protein (RYBP) and YY1 associated factor2 (YAF2). List of genes upregulated in the Rybp-/- and Yaf2-/- backgrounds, according to Zhao et al., 2018 [125] was used to produce Venn diagram showing the 27 common Rybp and Yaf2 upregulated genes. (B) Venn diagram showing the 65 targets of RYBP revealing top hits connected to germ cell development and meiosis. List of significantly upregulated genes in the Rybp mutant background from independent experiments, according to Ujhelly et al., 2015 [126], Rose et al., 2016 [94] and Zhao et al., 2018 [125]. (C) Gene onthology (GO) enrichment of the upregulated 65 targets of RYBP. GO enrichment analysis was performed for the 65 commonly upregulated genes in the Rybp mutant ES cells revealing top hits connecting to germ cell development and meiosis. (D) Key germ cell and meiotic genes are upregulated in the Rybp-/- background. Raw reads from genome-wide transcriptome analyses by Ujhelly et al., 2015 [126] was used to produce a scatter plot, plotting wild type (Rybp+/+) in the X-axis and Rybp-/- in the Y-axis. Highlighted dots in orange represent the germ-cell-specific genes upregulated in the Rybp-/- mutants. Nanog, which is highly upregulated in the Rybp-/- cells is indicated with a black arrow (Reads Per Kilobase Million, (RPKM): Rybp+/+-17524.93; Rybp-/--34448: Fold change-1.96) (E) Highlighted region from Figure 3D (Dotted box) is enlarged to show germ-cell-specific genes. (F) RYBP is present strongly at the mouse adult spermatogonia. Immunohistochemical analysis of adult mouse testis stained with hematoxylin and eosin (purple) and anti-RYBP antibody (brown) (Merck Millipore, Cat.No: AB3637, Darmstadt, Germany) showing the presence of RYBP in the primary and secondary spermatozoa. Strong expression in the spermatogonial stem cells is indicated by a black arrow.
Figure 4
Figure 4
Possible regulatory mechanisms of RYBP driving germ cell development. (A) Schematic representation illustrating that RYBP can interact with E2F transcription factor 2 and 3 (E2F2/E2F3) and YY1 transcription factor (YY1) to transcriptionally regulate Cell division cycle 6 (Cdc6) [89]. (B) Schematic representation illustrating that RYBP can interact with E2F6 and YY1 to repress genes such as MaeI, Staq3 and Smc1β [90]. (C) Schematic representation of a possible repression mechanism of RYBP via the E2F6 and DNA methyl transferase 3b (DNMT3B) on Tex11, Ddx4 and MaeI locus by recognizing the methylation mark at the CpG islands [201]. (D) Schematic representation of PCGF6, RYBP and OCT4/POU5F1 acting synergistically in order to activate Kdm2b [71].

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