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Comment |
Maternal DCAF13 Regulates Chromatin Tightness to Contribute to Embryonic Development. Liu Y et al. (2019) Maternal-zygotic transition (MZT) is critical for the developmental control handed from maternal products to newly synthesized zygotic genome in the earliest stage of embryogenesis. However, the spatiotemporal dynamic regulation of MZT by maternal factors is largely unknown. Here, we reported a novel maternal factor, DCAF13, which was highly expressed in growing oocyte nucleolus and had key maternal effects on oocyte and zygotic chromatin tightness during maternal to zygotic transition. DCAF13 specifically deleted in oocytes resulted in loose chromatin structure in fully grown germinal vesicle oocytes. Despite normal nuclear maturation in maternal DCAF13-deleted oocytes, the chromosomes at MII stage were not properly condensed. Consequently, the nuclear and nucleolar structure reorganized abnormally, and transcription was inactive in zygotic embryos. RNA-seq analysis of MII oocytes and 2-cell embryos demonstrated that the transcriptomes between knockout and control oocyte were similar, but the maternal DCAF13 deleted two-cell embryos showed a significant decrease in transcription. In addition, the maternal DCAF13-deleted embryos displayed arrest at the two-cell stage, which could not be rescued by injecting flag-Dcaf13 mRNA in the zygote. This revealed that DCAF13 was a unique maternal effect factor regulating the nucleolus.//////////////////
DCAF13 promotes pluripotency by negatively regulating SUV39H1 stability during early embryonic development. Zhang YL et al. (2018) Mammalian oocytes and zygotes have the unique ability to reprogram a somatic cell nucleus into a totipotent state. SUV39H1/2-mediated histone H3 lysine-9 trimethylation (H3K9me3) is a major barrier to efficient reprogramming. How SUV39H1/2 activities are regulated in early embryos and during generation of induced pluripotent stem cells (iPSCs) remains unclear. Since expression of the CRL4 E3 ubiquitin ligase in oocytes is crucial for female fertility, we analyzed putative CRL4 adaptors (DCAFs) and identified DCAF13 as a novel CRL4 adaptor that is essential for preimplantation embryonic development. Dcaf13 is expressed from eight-cell to morula stages in both murine and human embryos, and Dcaf13 knockout in mice causes preimplantation-stage mortality. Dcaf13 knockout embryos are arrested at the eight- to sixteen-cell stage before compaction, and this arrest is accompanied by high levels of H3K9me3. Mechanistically, CRL4-DCAF13 targets SUV39H1 for polyubiquitination and proteasomal degradation and therefore facilitates H3K9me3 removal and zygotic gene expression. Taken together, CRL4-DCAF13-mediated SUV39H1 degradation is an essential step for progressive genome reprogramming during preimplantation embryonic development.//////////////////
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Mutations |
2 mutations
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: Mammalian nucleolar protein DCAF13 is essential for ovarian follicle maintenance and oocyte growth by mediating rRNA processing. Zhang J et al. (2018) During mammalian oocyte growth, chromatin configuration transition from the nonsurrounded nucleolus (NSN) to surrounded nucleolus (SN) type plays a key role in the regulation of gene expression and acquisition of meiotic and developmental competence by the oocyte. Nonetheless, the mechanism underlying chromatin configuration maturation in oocytes is poorly understood. Here we show that nucleolar protein DCAF13 is an important component of the ribosomal RNA (rRNA)-processing complex and is essential for oocyte NSN-SN transition in mice. A conditional knockout of Dcaf13 in oocytes led to the arrest of oocyte development in the NSN configuration, follicular atresia, premature ovarian failure, and female sterility. The DCAF13 deficiency resulted in pre-rRNA accumulation in oocytes, whereas the total mRNA level was not altered. Further exploration showed that DCAF13 participated in the 18S rRNA processing in growing oocytes. The lack of 18S rRNA because of DCAF13 deletion caused a ribosome assembly disorder and then reduced global protein synthesis. DCAF13 interacted with a protein of the core box C/D ribonucleoprotein, fibrillarin, i.e., a factor of early pre-rRNA processing. When fibrillarin was knocked down in the oocytes from primary follicles, follicle development was inhibited as well, indicating that an rRNA processing defect in the oocyte indeed stunts chromatin configuration transition and follicle development. Taken together, these results elucidated the in vivo function of novel nucleolar protein DCAF13 in maintaining mammalian oogenesis.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: subfertile
Comment: The CRL4-DCAF13 ubiquitin E3 ligase supports oocyte meiotic resumption by targeting PTEN degradation. Zhang J et al. (2019) Cullin ring-finger ubiquitin ligase 4 (CRL4) has multiple functions in the maintenance of oocyte survival and meiotic cell cycle progression. DCAF13, a novel CRL4 adaptor, is essential for oocyte development. But the mechanisms by which CRL4-DCAF13 supports meiotic maturation remained unclear. In this study, we demonstrated that DCAF13 stimulates the meiotic resumption-coupled activation of protein synthesis in oocytes, partially by maintaining the activity of PI3K signaling pathway. CRL4-DCAF13 targets the polyubiquitination and degradation of PTEN, a lipid phosphatase that inhibits PI3K pathway as well as oocyte growth and maturation. Dcaf13 knockout in oocytes caused decreased CDK1 activity and impaired meiotic cell cycle progression and chromosome condensation defects. As a result, chromosomes fail to be aligned at the spindle equatorial plate, the spindle assembly checkpoint is activated, and most Dcaf13 null oocytes are arrested at the prometaphase I. The DCAF13-dependent PTEN degradation mechanism fits in as a missing link between CRL4 ubiquitin E3 ligase and PI3K pathway, both of which are crucial for translational activation during oocyte GV-MII transition.//////////////////
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