CBX2 is required to stabilize the testis pathway by repressing Wnt signaling. Garcia-Moreno SA et al. (2019) XX and XY fetal gonads are initially bipotential, poised between the ovary and testis fate. Multiple lines of evidence suggest that commitment to testis fate requires the repression of genes associated with ovary fate. It was previously shown that loss of CBX2, the subunit of the Polycomb Repressive Complex 1 (PRC1) that binds H3K27me3 and mediates silencing, leads to ovary development in XY mice and humans. While it had been proposed that CBX2 is an activator of the testis-determining gene Sry, we investigated the alternative possibility that CBX2 has a direct role as a repressor of the antagonistic ovary-promoting pathway. To investigate this possibility, we developed a quantitative genome-wide profile of the repressive histone mark H3K27me3 and its active counterpart H3K4me3 in isolated XY and XX gonadal supporting cells before and after sex determination. We show that testis and ovary sex-determining (SD) genes are bivalent before sex determination, providing insight into how the bipotential state of the gonad is established at the epigenetic level. After sex determination, many SD genes of the alternate pathway remain bivalent, possibly contributing to the ability of these cells to transdifferentiate even in adults. The finding that many genes in the Wnt signaling pathway were targeted for H3K27me3-mediated repression in Sertoli cells led us to test whether deletion of Wnt4 could rescue testis development in Cbx2 mutants. We show that Sry expression and testis development were rescued in XY Cbx2-/-;Wnt4-/- mice. Furthermore, we show that CBX2 directly binds the downstream Wnt signaler Lef1, an ovary-promoting gene that remains bivalent in Sertoli cells. Our results suggest that stabilization of the testis fate requires CBX2-mediated repression of bivalent ovary-determining genes, which would otherwise block testis development.//////////////////
NCBI Summary:
This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2010]
General function
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Cellular localization
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Ovarian function
Germ cell development
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The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach. Bouazzi L et al. (2019) The chromobox homolog 2 (CBX2) was found to be important for human testis development, but its role in the human ovary remains elusive. We conducted a genome-wide analysis based on DNA adenine methyltransferase identification (DamID) and RNA sequencing strategies to investigate CBX2 in the human granulosa cells. Functional analysis revealed that CBX2 was upstream of genes contributing to ovarian function like folliculogenesis and steroidogenesis (i.e. ESR1, NRG1, AKR1C1, PTGER2, BMP15, BMP2, FSHR and NTRK1/2). We identified CBX2 regulated genes associated with polycystic ovary syndrome (PCOS) such as TGFβ, MAP3K15 and DKK1, as well as genes implicated in premature ovarian failure (POF) (i.e. POF1B, BMP15 and HOXA13) and the pituitary deficiency (i.e. LHX4 and KISS1). Our study provided an excellent opportunity to identify genes surrounding CBX2 in the ovary and might contribute to the understanding of ovarian physiopathology causing infertility in women.////////////////// Role of Polycomb Group Protein Cbx2/M33 in Meiosis Onset and Maintenance of Chromosome Stability in the Mammalian Germline. Baumann C et al. Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice results in homeotic transformations of the axial skeleton, growth retardation and male-to-female sex reversal. In this study, we tested whether Cbx2 is involved in the control of chromatin remodeling processes during meiosis. Our analysis revealed sex reversal in 28.6% of XY(-/-) embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia. Notably, germ cells recovered from Cbx2((XY-/-)) testes on day 18.5 of fetal development exhibited premature meiosis onset with synaptonemal complex formation suggesting a role for Cbx2 in the control of meiotic entry in male germ cells. Mutant females exhibited small ovaries with significant germ cell loss and a high proportion of oocytes with abnormal synapsis and non-homologous interactions at the pachytene stage as well as formation of univalents at diplotene. These defects were associated with failure to resolve DNA double strand breaks marked by persistent ?H2AX and Rad51 foci at the late pachytene stage. Importantly, two factors required for meiotic silencing of asynapsed chromatin, ubiquitinated histone H2A (ubH2A) and the chromatin remodeling protein BRCA1, co-localized with fully synapsed chromosome axes in the majority of Cbx2((-/-)) oocytes. These results provide novel evidence that Cbx2 plays a critical and previously unrecognized role in germ cell viability, meiosis onset and homologous chromosome synapsis in the mammalian germline.
Expression regulated by
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Ovarian localization
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Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Role of Polycomb Group Protein Cbx2/M33 in Meiosis Onset and Maintenance of Chromosome Stability in the Mammalian Germline. Baumann C et al. Polycomb group proteins (PcG) are major epigenetic regulators, essential for establishing heritable expression patterns of developmental control genes. The mouse PcG family member M33/Cbx2 (Chromobox homolog protein 2) is a component of the Polycomb-Repressive Complex 1 (PRC1). Targeted deletion of Cbx2/M33 in mice results in homeotic transformations of the axial skeleton, growth retardation and male-to-female sex reversal. In this study, we tested whether Cbx2 is involved in the control of chromatin remodeling processes during meiosis. Our analysis revealed sex reversal in 28.6% of XY(-/-) embryos, in which a hypoplastic testis and a contralateral ovary were observed in close proximity to the kidney, while the remaining male mutant fetuses exhibited bilateral testicular hypoplasia. Notably, germ cells recovered from Cbx2((XY-/-)) testes on day 18.5 of fetal development exhibited premature meiosis onset with synaptonemal complex formation suggesting a role for Cbx2 in the control of meiotic entry in male germ cells. Mutant females exhibited small ovaries with significant germ cell loss and a high proportion of oocytes with abnormal synapsis and non-homologous interactions at the pachytene stage as well as formation of univalents at diplotene. These defects were associated with failure to resolve DNA double strand breaks marked by persistent ?H2AX and Rad51 foci at the late pachytene stage. Importantly, two factors required for meiotic silencing of asynapsed chromatin, ubiquitinated histone H2A (ubH2A) and the chromatin remodeling protein BRCA1, co-localized with fully synapsed chromosome axes in the majority of Cbx2((-/-)) oocytes. These results provide novel evidence that Cbx2 plays a critical and previously unrecognized role in germ cell viability, meiosis onset and homologous chromosome synapsis in the mammalian germline.