|
Comment |
CFP1 Regulates Histone H3K4 Trimethylation and Developmental Potential in Mouse Oocytes. Yu C et al. (2017) Trimethylation of histone H3 at lysine-4 (H3K4me3) is associated with eukaryotic gene promoters and poises their transcriptional activation during development. To examine the in vivo function of H3K4me3 in the absence of DNA replication, we deleted CXXC finger protein 1 (CFP1), the DNA-binding subunit of the SETD1 histone H3K4 methyltransferase, in developing oocytes. We find that CFP1 is required for H3K4me3 accumulation and the deposition of histone variants onto chromatin during oocyte maturation. Decreased H3K4me3 in oocytes caused global downregulation of transcription activity. Oocytes lacking CFP1 failed to complete maturation and were unable to gain developmental competence after fertilization, due to defects in cytoplasmic lattice formation, meiotic division, and maternal-zygotic transition. Our study highlights the importance of H3K4me3 in continuous histone replacement for transcriptional regulation, chromatin remodeling, and normal developmental progression in a non-replicative system.//////////////////
|
|
Mutations |
3 mutations
Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: CFP1 coordinates histone H3 lysine-4 trimethylation and meiotic cell cycle progression in mouse oocytes. Sha QQ et al. (2018) Trimethylation of histone H3 on lysine-4 (H3K4me3) is associated with gene-regulatory elements, but its transcription-independent function in cell division is unclear. CxxC-finger protein-1 (CFP1) is a major mediator of H3K4 trimethylation in mouse oocytes. Here we report that oocyte-specific knockout of Cxxc1, inhibition of CFP1 function, or abrogation of H3K4 methylation in oocytes each causes a delay of meiotic resumption as well as metaphase I arrest owing to defective spindle assembly and chromosome misalignment. These phenomena are partially attributed to insufficient phosphorylation of histone H3 at threonine-3. CDK1 triggers cell division-coupled degradation and inhibitory phosphorylation of CFP1. Preventing CFP1 degradation and phosphorylation causes CFP1 accumulation on chromosomes and impairs meiotic maturation and preimplantation embryo development. Therefore, CFP1-mediated H3K4 trimethylation provides 3a permission signal for the G2-M transition. Dual inhibition of CFP1 removes the SETD1-CFP1 complex from chromatin and ensures appropriate chromosome configuration changes during meiosis and mitosis.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: CFP1-dependent histone H3K4 trimethylation in murine oocytes facilitates ovarian follicle recruitment and ovulation in a cell-nonautonomous manner. Sha QQ et al. (2019) CxxC-finger protein 1 (CFP1)-mediated trimethylated histone H3 at lysine-4 (H3K4me3) during oocyte development enables the oocyte genome to establish the competence to generate a new organism. Nevertheless, it remains unclear to which extent this epigenetic modification forms an instructive component of ovarian follicle development. We investigated the ovarian functions using an oocyte-specific Cxxc1 knockout mouse model, in which the H3K4me3 accumulation is downregulated in oocytes of developing follicles. CFP1-dependent H3K4 trimethylation in oocytes was necessary to maintain the expression of key paracrine factors and to facilitate the communication between an oocyte and the surrounding granulosa cells. The distinct gene expression patterns in cumulus cells within preovulatory follicles were disrupted by the Cxxc1 deletion in oocytes. Both follicle growth and ovulation were compromised after CFP1 deletion, because Cxxc1 deletion in oocytes indirectly impaired essential signaling pathways in granulosa cells that mediate the functions of follicle-stimulating hormone and luteinizing hormone. Therefore, CFP1-regulated epigenetic modification of the oocyte genome influences the responses of ovarian follicles to gonadotropin in a cell-nonautonomous manner.//////////////////
Species: mouse
Mutation name:
type: null mutation
fertility: infertile - ovarian defect
Comment: CxxC finger protein 1-mediated histone H3 lysine-4 trimethylation is essential for proper meiotic crossover formation in mice. Jiang Y et al. (2020) CXXC finger protein 1 (CFP1) binds to the CpG islands and mediates the SETD1 complex to deposit H3K4me3. CFP1 is also predicted to recruit H3K4me3 marked regions to the chromosome axis for DSB generation in the prophase of meiosis. So we deleted CFP1 before the onset of meiosis with Stra8-Cre The conditional knockout mice were completely sterile with spermatogenesis arrested at MII. The knockout of CFP1 caused H3K4me3 level decreased from pachytene to MII stage and caused transcriptional disorder. Many spermatogenesis pathway genes expressed ahead of time leading to abnormal acrosome formation in arrested MII cells. In meiotic prophase, deletion of CFP1 caused delayed DSB repair and improper crossover formation in pachytene and more than half diplotene cells with precocious homologous chromosomes segregation in both male and female meiosis. CFP1 deletion also led to a significant decrease of H3K4me3 enrichment at DMC1-binding sites, which might compromise DSB generation. Taken together, our results showed that CFP1 is essential for proper meiotic crossover formation in mice and suggested that CFP1-mediated H3K4me3 plays an essential role in meiotic prophase of spermatogenesis and oogenesis.//////////////////
|