A histone H3 methyltransferase controls epigenetic events required for meiotic prophase

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Abstract
Meiosis is a unique cell division that is necessary for sexual reproduction; it produces functional haploid gametes and shuffles genomic information. Progression through meiosis is controlled by the proper orchestration of a number of meiotic genes. A candidate gene for regulating meiotic gene expression has now been identified. Meisetz, encoding a meiosis-specific histone H3 lysine 4-specific trimethyltransferase, is essential for meiotic recombination between homologous chromosomes in mice. Meisetz has essential functions in spermatocytes through epigenetic modification of chromatin, the first instance of a gene regulating epigenetic control of gene expression during meiotic progression. Epigenetic modifications of histones regulate gene expression and chromatin structure1,2. Here we show that Meisetz (meiosis-induced factor containing a PR/SET domain and zinc-finger motif) is a histone methyltransferase that is important for the progression of early meiotic prophase. Meisetz transcripts are detected only in germ cells entering meiotic prophase in female fetal gonads and in postnatal testis. Notably, Meisetz has catalytic activity for trimethylation, but not mono- or dimethylation, of lysine 4 of histone H3, and a transactivation activity that depends on its methylation activity. Mice in which the Meisetz gene is disrupted show sterility in both sexes due to severe impairment of the double-stranded break repair pathway, deficient pairing of homologous chromosomes and impaired sex body formation. In Meisetz-deficient testis, trimethylation of lysine 4 of histone H3 is attenuated and meiotic gene transcription is altered. These findings indicate that meiosis-specific epigenetic events in mammals are crucial for proper meiotic progression.