Successful reproduction requires an oocyte competent to sustain early embryo development. By the end of oogenesis, the oocyte has entered a transcriptionally silenced state, the mechanisms and significance of which remain poorly understood. Histone H3.3, a histone H3 variant, has unique cell cycle-independent functions in chromatin structure and gene expression. Here, we have characterised the H3.3 chaperone Hira/Cabin1/Ubn1 complex, showing that loss of function of any of these subunits causes early embryogenesis failure in mouse. Transcriptome and nascent RNA analyses revealed that transcription is aberrantly silenced in mutant oocytes. Histone marks, including H3K4me3 and H3K9me3, are reduced and chromatin accessibility is impaired in Hira/Cabin1 mutants. Misregulated genes in mutant oocytes include Zscan4d, a two-cell specific gene involved in zygote genome activation. Overexpression of Zscan4 in the oocyte partially recapitulates the phenotypes of Hira mutants and Zscan4 knockdown in Cabin1 mutant oocytes partially restored their developmental potential, illustrating that temporal and spatial expression of Zscan4 is fine-tuned at the oocyte-to-embryo transition. Thus, the H3.3 chaperone Hira complex has a maternal effect function in oocyte developmental competence and embryogenesis, through modulating chromatin condensation and transcriptional quiescence.

• Klíčová slova
• Competent oocyte, Hira complex, Histone H3.3, Oocyte-to-embryo transition, Zygotic genome activation,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• chromatin metabolismus   MeSH
• embryonální vývoj genetika   MeSH
• genový knockdown MeSH
• histonové chaperony genetika   metabolismus   MeSH
• histony metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši transgenní MeSH
• myši MeSH
• oocyty růst a vývoj   metabolismus   MeSH
• oogeneze genetika   MeSH
• proteiny buněčného cyklu genetika   metabolismus   MeSH
• signální transdukce genetika   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• zvířata MeSH
• zygota metabolismus   MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• Cabin1 protein, mouse MeSH Prohlížeč
• chromatin MeSH
• Hira protein, mouse MeSH Prohlížeč
• histonové chaperony MeSH
• histony MeSH
• proteiny buněčného cyklu MeSH
• transkripční faktory MeSH
• Zscan4d protein, mouse MeSH Prohlížeč

During meiosis, pairing of homologous chromosomes and their synapsis are essential prerequisites for normal male gametogenesis. Even limited autosomal asynapsis often leads to spermatogenic impairment, the mechanism of which is not fully understood. The present study was aimed at deliberately increasing the size of partial autosomal asynapsis and analysis of its impact on male meiosis. For this purpose, we studied the effect of t(12) haplotype encompassing four inversions on chromosome 17 on mouse autosomal translocation T(16;17)43H (abbreviated T43H). The T43H/T43H homozygotes were fully fertile in both sexes, while +/T43H heterozygous males, but not females, were sterile with meiotic arrest at late pachynema. Inclusion of the t(12) haplotype in trans to the T43H translocation resulted in enhanced asynapsis of the translocated autosome, ectopic phosphorylation of histone H2AX, persistence of RAD51 foci, and increased gene silencing around the translocation break. Increase was also on colocalization of unsynapsed chromatin with sex body. Remarkably, we found that transcriptional silencing of the unsynapsed autosomal chromatin precedes silencing of sex chromosomes. Based on the present knowledge, we conclude that interference of meiotic silencing of unsynapsed autosomes with meiotic sex chromosome inactivation is the most likely cause of asynapsis-related male sterility.

• MeSH
• biologické modely MeSH
• chromatin metabolismus   fyziologie   MeSH
• chromozomy genetika   metabolismus   MeSH
• genetická transkripce genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• meióza genetika   fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• párování chromozomů genetika   MeSH
• pohlavní chromozomy genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• translokace genetická genetika   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH

Heterozygosity for certain mouse and human chromosomal rearrangements is characterized by the incomplete meiotic synapsis of rearranged chromosomes, by their colocalization with the XY body in primary spermatocytes, and by male-limited sterility. Previously, we argued that such X-autosomal associations could interfere with meiotic sex chromosome inactivation. Recently, supporting evidence has reported modifications of histones in rearranged chromosomes by a process called the meiotic silencing of unsynapsed chromatin (MSUC). Here, we report on the transcriptional down-regulation of genes within the unsynapsed region of the rearranged mouse chromosome 17, and on the subsequent disturbance of X chromosome inactivation. The partial transcriptional suppression of genes in the unsynapsed chromatin was most prominent prior to the mid-pachytene stage of primary spermatocytes. Later, during the mid-late pachytene, the rearranged autosomes colocalized with the XY body, and the X chromosome failed to undergo proper transcriptional silencing. Our findings provide direct evidence on the MSUC acting at the mRNA level, and implicate that autosomal asynapsis in meiosis may cause male sterility by interfering with meiotic sex chromosome inactivation.

• MeSH
• chromatin genetika   MeSH
• chromozom X genetika   MeSH
• down regulace MeSH
• genová přestavba MeSH
• inaktivace chromozomu X * MeSH
• lidé MeSH
• meióza genetika   MeSH
• mužská infertilita genetika   MeSH
• myši inbrední C57BL MeSH
• myši kongenní MeSH
• myši MeSH
• spermatocyty cytologie   metabolismus   MeSH
• spermatogeneze genetika   MeSH
• translokace genetická MeSH
• umlčování genů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chromatin MeSH