ABSTRACT
The most significant feature of meiosis is the recombination process during prophase I. CXXC finger protein 1 (CXXC1) binds to CpG islands and mediates the deposition of H3K4me3 by the SETD1 complex. CXXC1 is also predicted to recruit H3K4me3-marked regions to the chromosome axis for the generation of double-strand breaks (DSBs) in the prophase of meiosis. Therefore, we deleted Cxxc1 before the onset of meiosis with Stra8-Cre. The conditional knockout mice were completely sterile with spermatogenesis arrested at MII. Knockout of Cxxc1 led to a decrease in the H3K4me3 level from the pachytene to the MII stage and caused transcriptional disorder. Many spermatogenesis pathway genes were expressed early leading to abnormal acrosome formation in arrested MII cells. In meiotic prophase, deletion of Cxxc1 caused delayed DSB repair and improper crossover formation in cells at the pachytene stage, and more than half of the diplotene cells exhibited precocious homologous chromosome segregation in both male and female meiosis. Cxxc1 deletion also led to a significant decrease of H3K4me3 enrichment at DMC1-binding sites, which might compromise DSB generation. Taken together, our results show that CXXC1 is essential for proper meiotic crossover formation in mice and suggest that CXXC1-mediated H3K4me3 plays an essential role in meiotic prophase of spermatogenesis and oogenesis.
Footnotes
Author contributions
Conceptualization: C.Y., Q.-Q.S., M.-H.T., H.-Y.F.; Methodology: M.-H.T., L.S.; Software: Y.-Z.Z.; Formal analysis: Y.-Z.Z., L.S.; Investigation: Y.J., H.-Y.Z., Z.L., C.Y.; Resources: M.-H.T.; Data curation: L.S.; Writing - original draft: Y.J., H.-Y.F.; Writing - review & editing: H.-Y.F.; Supervision: M.-H.T., L.S., H.-Y.F.; Project administration: Q.-Q.S., H.-Y.F.; Funding acquisition: H.-Y.F.
Funding
National Natural Science Foundation of China [31528016, 31871478, 31371449, 31671558]; National Key Research and Developmental Program of China [2016YFC1000600, 2017YFC1001500]; Natural Science Foundation of Zhejiang Province [LR18C060001]; Primary Research and Development Plan of Zhejiang Province [2017C03022]; Cao Guangbiao High Science and Technology Foundation, Zhejiang University.
Data availability
RNA-seq and ChIP-seq data have been deposited in the NCBI Gene Expression Omnibus database under accession number GSE133636. See http://genome.ucsc.edu/s/yezhang_zhu/Spermatocyte%2DCxxc1%2DRNA%2Dseq for the UCSC genome browser session for RNA-seq data. See http://genome.ucsc.edu/s/yezhang_zhu/Spermatocyte%2DCxxc1%2DChIP%2Dseq for the UCSC genome browser session for ChIP-seq data.
