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Eukaryotic translation elongation factor EEF1G orchestrates the translational program to ensure meiotic progression in transcriptionally silent spermatocytes [Ribo-Seq]

ABSTRACT: During meiotic prophase I, mammalian spermatocytes face a critical challenge that they need to synthesize recombination and synapsis proteins while global transcriptional suppression occurs at leptotene/zygotene stages. Here, we identify a spermatogenic cell highly expressed protein, eukaryotic translation elongation factor 1 gamma (EEF1G), as a master regulator of translational adaptation in mouse spermatocytes. Germ cell-specific Eef1g knockout causes complete male infertility due to the meiotic arrest at the zygotene stage, which is characterized by unresolved DNA double-strand breaks, failed homologous chromosome synapsis, and abolished crossover formation. Mechanistically, EEF1G can interact with ribosome proteins and RNA-binding factors. Ribosome profiling reveals that EEF1G deficiency reduces ribosome processivity, leading to ribosomal stalling and decreased protein production. Consequently, proteomic analyses show a specific decrease of synapsis (e.g., SYCP1/SYCE1) and recombination (e.g., MSH4/TEX11) proteins. This study establishes EEF1G as a critical coordinator of spatial translation in transcriptionally silent spermatocytes, bridging limited mRNA engagement to explosive protein synthesis for meiotic progression. Our work challenges traditional views of meiotic control by highlighting translation elongation, not just as a housekeeping process, but as a stage-specific regulator of germ cell development.

ORGANISM(S): Mus musculus

PROVIDER: GSE307886 | GEO | 2025/09/13

REPOSITORIES: GEO

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Project description:Repro9 in an allele of Mybl1 (A-Myb) transcription factor obtained in ENU screen to identify alleles causing mouse infertility. Repro9/repro9 mutant males are infertile due to meiotic arrest at pachytene stage. Mutants show wide range of abnormalities including inefficient chromosome synapsis, sex body formation and progression through meiotic cycle. Females are unaffected. To determine genes transcriptionally regulated by MYBL1 we analyzed gene expression profiles of wild type and repro9/repro9 mutant testis at 14 and 17 days postpartum. Analysis revealed many misregulated genes, in majority downregulated, at day 14 pp and even more at day 17 pp, probably due to secondary effects of meiotic arrest. Significantly misregulated genes were characterized by Gene Ontology. Comparative gene expression analysis uncovered potential targets of MYBL1 regulation that play roles in regulation of transcription, cell cycle, apoptosis, protein phosphorylation and ubiquitination, chromosome organization and others. Abstract:The transcriptional regulation of mammalian meiosis is poorly characterized, due to few genetic and ex vivo models. From a genetic screen, we identify the transcription factor MYBL1 as a male-specific master regulator of several critical meiotic processes. Spermatocytes bearing a novel separation-of-function allele (Mybl1repro9) had subtle defects in autosome synapsis in pachynema, a high incidence of unsynapsed sex chromosomes, incomplete double strand break (DSB) repair on synapsed pachytene chromosomes, and a lack of crossing-over. MYBL1 protein appears in pachynema, and its mutation caused specific alterations in expression of diverse genes, including some translated postmeiotically. These data, coupled with chromatin immunoprecipitation (ChIP-chip) experiments and bioinformatic analysis of promoters, identified direct targets of MYBL1 regulation. Meiosis in mutant females appears unaffected. These results reveal that MYBL1 is a master regulator of meiotic genes that are involved in multiple processes in spermatocytes, including chromosome synapsis, recombination, and cell cycle progression through pachynema. RNA was extracted from wt and repro9/repro9 mutant testis from 14 and 17 days old mice. This two time points were selected for sample enrichment in early/midpachytene and latepachytene/diplotene spermatocytes, respectively. Total testis RNA from wild-type (≥3) and mutant (≥3) mice was reverse-transcribed into double stranded cDNA, and biotin-labeled cRNA (GeneChip IVT labeling kit, Affymetrix, Santa Clara, CA) was hybridized to Affymetrix mouse genome 430 2.0 GeneChips containing. The raw data was processed using Affymetrix GCOS software. Two-way ANOVA analysis resolved differentially expressed (DE) genes either between genotypes and/or days using MeV(version 4.6.1) on log2-transformed expression values. Results were multiple test corrected with the Benjamini-Hochberg method to control the false discovery rate (FDR) in R. ~800 genes significant at FDR<=0.025 were selected as differentially expressed for downstream analysis.

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Eukaryotic translation elongation factor EEF1G orchestrates the translational program to ensure meiotic progression in transcriptionally silent spermatocytes [Ribo-Seq]

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