E2f6-mediated repression of the meiotic<i>Stag3</i>and<i>Smc1β</i>genes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b

Leseva, Milena; Santostefano, Katherine E.; Rosenbluth, Amy L; Hamazaki, Takashi; Terada, Naohiro

doi:10.4161/epi.25522

Cited by 14 publications

(9 citation statements)

References 29 publications

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“…10 In female mice, the Ant4 gene was expressed in embryonic ovaries in which prophase 1 proceeds along with the control meiosis-specific gene Sycp3 . Indeed, we previously demonstrated that repression of the Ant4 gene during somatic cell specification is, at least in part, regulated by the E2F6 transcriptional repressor, and this mechanism is apparently conserved in many other meiosis-specific genes, including Stag3 and Smc1 β, 17,18 further supporting the finding here. The meiosis-specific expression appears to be governed by flanking regions of the Ant4 gene, as the BAC transgene showed identical expression profiles to the endogenous Ant4 gene.…”

Section: Discussionsupporting

confidence: 88%

Adenine Nucleotide Translocase 4 Is Expressed Within Embryonic Ovaries and Dispensable During Oogenesis

et al. 2015

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Adenine nucleotide translocase (Ant) facilitates the exchange of adenosine triphosphate across the mitochondrial inner membrane and plays a critical role for bioenergetics in eukaryotes. Mice have 3 Ant paralogs, Ant1 (Slc25a4), Ant2 (Slc25a5), and Ant4 (Slc25a31), which are expressed in a tissue-dependent manner. We previously identified that Ant4 was expressed exclusively in testicular germ cells in adult mice and essential for spermatogenesis and subsequently male fertility. Further investigation into the process of spermatogenesis revealed that Ant4 was particularly highly expressed during meiotic prophase I and indispensable for normal progression of leptotene spermatocytes to the stages thereafter. In contrast, the expression and roles of Ant4 in female germ cells have not previously been elucidated. Here, we demonstrate that the Ant4 gene is expressed during embryonic ovarian development during which meiotic prophase I occurs. We confirmed embryonic ovary-specific Ant4 expression using a bacterial artificial chromosome transgene. In contrast to male, however, Ant4 null female mice were fertile although the litter size was slightly decreased. They showed apparently normal ovarian development which was morphologically indistinguishable from the control animals. These data indicate that Ant4 is a meiosis-specific gene expressed during both male and female gametogenesis however indispensable only during spermatogenesis and not oogenesis. The differential effects of Ant4 depletion within the processes of male and female gametogenesis may be explained by meiosis-specific inactivation of the X-linked Ant2 gene in male, a somatic paralog of the Ant4 gene.

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Section: Discussionsupporting

confidence: 88%

Adenine Nucleotide Translocase 4 Is Expressed Within Embryonic Ovaries and Dispensable During Oogenesis

et al. 2015

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“…Otx2, sox3, and sox10 factors, involved in NC differentiation and neural development, may not co-operate with foxd3 to mediate repression but rather compete for underlying binding sequences to promote multipotent NC cell differentiation (Beby and Lamonerie, 2013, Carney et al., 2006, Dee et al., 2008). Conversely, e2f6 factor is known to function as a transcriptional repressor that associates with Polycomb repressive complexes (PRC1 and PRC2) (Gaubatz et al., 1998, Leseva et al., 2013, Trimarchi et al., 2001). We explored e2f6/foxd3 co-operation in transcriptional repression by scanning four different e2f6 motifs across all foxd3-bound regions associated with the genes upregulated in 14ss foxd3 -mutant embryos (Figure 3E) and found that 82.3% of them were significantly enriched for e2f6 binding (chi-square test; ∗∗∗ p < 0.0004).…”

Section: Resultsmentioning

confidence: 99%

From Pioneer to Repressor: Bimodal foxd3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo

et al. 2018

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SummaryThe neural crest (NC) is a transient embryonic stem cell-like population characterized by its multipotency and broad developmental potential. Here, we perform NC-specific transcriptional and epigenomic profiling of foxd3-mutant cells in vivo to define the gene regulatory circuits controlling NC specification. Together with global binding analysis obtained by foxd3 biotin-ChIP and single cell profiles of foxd3-expressing premigratory NC, our analysis shows that, during early steps of NC formation, foxd3 acts globally as a pioneer factor to prime the onset of genes regulating NC specification and migration by re-arranging the chromatin landscape, opening cis-regulatory elements and reshuffling nucleosomes. Strikingly, foxd3 then gradually switches from an activator to its well-described role as a transcriptional repressor and potentially uses differential partners for each role. Taken together, these results demonstrate that foxd3 acts bimodally in the neural crest as a switch from “permissive” to “repressive” nucleosome and chromatin organization to maintain multipotency and define cell fates.

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“…Some target genes such as Smc1b and Meioc acquire only partial promoter CGI methylation and are much more derepessed in E2f6 −/− embryos compared to Dnmt3a/b mutant embryos, suggesting that E2F6 induces long-term repression of germline genes through multiple epigenetic functions. These alternative mechanisms could involve polycomb-mediated H3K27 methylation, which is involved in silencing of the Smc1b gene in mouse ESCs 57 .…”

Section: Discussionmentioning

confidence: 99%

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

et al. 2021

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In mouse development, long-term silencing by CpG island DNA methylation is specifically targeted to germline genes; however, the molecular mechanisms of this specificity remain unclear. Here, we demonstrate that the transcription factor E2F6, a member of the polycomb repressive complex 1.6 (PRC1.6), is critical to target and initiate epigenetic silencing at germline genes in early embryogenesis. Genome-wide, E2F6 binds preferentially to CpG islands in embryonic cells. E2F6 cooperates with MGA to silence a subgroup of germline genes in mouse embryonic stem cells and in embryos, a function that critically depends on the E2F6 marked box domain. Inactivation of E2f6 leads to a failure to deposit CpG island DNA methylation at these genes during implantation. Furthermore, E2F6 is required to initiate epigenetic silencing in early embryonic cells but becomes dispensable for the maintenance in differentiated cells. Our findings elucidate the mechanisms of epigenetic targeting of germline genes and provide a paradigm for how transient repression signals by DNA-binding factors in early embryonic cells are translated into long-term epigenetic silencing during mouse development.

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E2f6-mediated repression of the meioticStag3andSmc1βgenes during early embryonic development requires Ezh2 and not the de novo methyltransferase Dnmt3b

Cited by 14 publications

References 29 publications

Adenine Nucleotide Translocase 4 Is Expressed Within Embryonic Ovaries and Dispensable During Oogenesis

Adenine Nucleotide Translocase 4 Is Expressed Within Embryonic Ovaries and Dispensable During Oogenesis

From Pioneer to Repressor: Bimodal foxd3 Activity Dynamically Remodels Neural Crest Regulatory Landscape In Vivo

E2F6 initiates stable epigenetic silencing of germline genes during embryonic development

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