Abstract
Histone H3K4 methylation is a feature of meiotic recombination hotspots shared by many organisms including plants and mammals. Meiotic recombination is initiated by programmed double-strand break (DSB) formation that in budding yeast takes place in gene promoters and is promoted by histone H3K4 di/trimethylation. This histone modification is recognized by Spp1, a PHD finger containing protein that belongs to the conserved histone H3K4 methyltransferase Set1 complex. During meiosis, Spp1 binds H3K4me3 and interacts with a DSB protein, Mer2, to promote DSB formation close to gene promoters. How Set1 complex- and Mer2- related functions of Spp1 are connected is not clear. Here, combining genome-wide localization analyses, biochemical approaches and the use of separation of function mutants, we show that Spp1 is present within two distinct complexes in meiotic cells, the Set1 and the Mer2 complexes. Disrupting the Spp1-Set1 interaction mildly decreases H3K4me3 levels and does not affect meiotic recombination initiation. Conversely, the Spp1-Mer2 interaction is required for normal meiotic recombination initiation, but dispensable for Set1 complex-mediated histone H3K4 methylation. Finally, we provide evidence that Spp1 preserves normal H3K4me3 levels independently of the Set1 complex. We propose a model where Spp1 works in three ways to promote recombination initiation: first by depositing histone H3K4 methylation (Set1 complex), next by “reading” and protecting histone H3K4 methylation, and finally by making the link with the chromosome axis (Mer2-Spp1 complex). This work deciphers the precise roles of Spp1 in meiotic recombination and opens perspectives to study its functions in other organisms where H3K4me3 is also present at recombination hotspots.
Highlights
In sexually reproducing organisms, recombination between homologous chromosomes at meiosis plays an important role to form gametes with a normal chromosome content
Recombination events between homologous chromosomes are triggered by the programmed formation of DNA breaks, which occur preferentially at places called hotspots
Meiotic recombination is initiated by the programmed formation of DNA double-strand breaks (DSBs) catalyzed by the conserved Spo11 protein together with largely conserved accessory DSB proteins [1,2,3] and is required to promote genetic diversity and accurate homolog segregation [4]
Summary
Recombination between homologous chromosomes at meiosis plays an important role to form gametes with a normal chromosome content. The vast majority of meiotic DSBs occur in the ~ 140 bp nucleosome depleted regions (NDR) at gene promoters, close to nucleosomes bearing the histone H3K4me modification [6, 8]. The tendency of meiotic recombination to occur in gene promoters and H3K4me regions is conserved among many organisms such as dogs, plants and birds [9,10,11]. Meiotic recombination occurs at H3K4me sites, but only those created by the meiotic-specific histone H3K4 methyltransferase, PRDM9 [12,13,14]. The mutation of Prdm in mice redirects meiotic recombination events towards gene promoters and H3K4me3 [16] as if PRDM9 had a dominant role over the default promoter/histone H3K4me conserved pathway
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