The COMPASS Subunit Spp1 Links Histone Methylation to Initiation of Meiotic Recombination

Abstract

During meiosis, combinatorial associations of genetic traits arise from homologous recombination between parental chromosomes. Histone H3 lysine 4 trimethylation marks meiotic recombination hotspots in yeast and mammals, but how this ubiquitous chromatin modification relates to the initiation of double-strand breaks (DSBs) dependent on Spo11 remains unknown. Here, we show that the tethering of a PHD-containing protein, Spp1 (a component of the COMPASS complex), to recombinationally cold regions is sufficient to induce DSB formation. Furthermore, we found that Spp1 physically interacts with Mer2, a key protein of the differentiated chromosomal axis required for DSB formation. Thus, by interacting with H3K4me3 and Mer2, Spp1 promotes recruitment of potential meiotic DSB sites to the chromosomal axis, allowing Spo11 cleavage at nearby nucleosome-depleted regions.

High-Resolution Global Analysis of the Influences of Bas1 and Ino4 Transcription Factors on Meiotic DNA Break Distributions in Saccharomyces cerevisiae

“…Thus, changes in the level of this histone modification in TF mutants provide no predictive power for changes in DSB frequency. This finding fits with the observation that, even though H3K4me3 promotes Spo11 activity in most promoter regions (84% of DSB sites exhibited a severely reduced DSB frequency in the absence of H3K4me3) Acquaviva et al 2013;Sommermeyer et al 2013), quantitative measures of H3K4me3 correlate poorly if at all with DSB hotspot strength (Tischfield and Keeney 2012). …”

“…This and other observations have led to a "tethered loop-axis complex" model in which DSBs are formed in loop segments captured by axis-associated DSB machinery (Blat et al 2002;Panizza et al 2011) (Figure 6A). Recently, it was discovered that the DSB-promoting protein Mer2 interacts with Spp1, a protein containing a PHD (Plant Homeo Domain) finger that binds H3K4me3 marks and may thereby tether the chromatin loop to the axis, promoting DSB formation in nucleosome-depleted regions in loops (Acquaviva et al 2013;Sommermeyer et al 2013). Thus, one hypothesis to account for altered DSB frequencies could be that deletion of TFs alters the H3K4me3 modification status around certain promoters and thereby affects Spp1-dependent targeting efficiency.…”

“…Most hotspots in S. cerevisiae coincide with the nucleosome-depleted regions at gene promoters (Wu and Lichten 1994;Baudat and Nicolas 1997;Pan et al 2011). The global DSB landscape is shaped by a hierarchical combination of factors, including whole chromosome variation, large subchromosomal domains, presence of cohesins and other chromosome structure proteins, local chromatin structure, and histone modification (Lichten and Goldman 1995;Petes 2001;Kauppi et al 2004;Lichten and de Massy 2011;Pan et al 2011;Acquaviva et al 2013;de Massy 2013;Sommermeyer et al 2013).…”

“…Most hotspots in S. cerevisiae coincide with the nucleosome-depleted regions at gene promoters (Wu and Lichten 1994;Baudat and Nicolas 1997;Pan et al 2011). The global DSB landscape is shaped by a hierarchical combination of factors, including whole chromosome variation, large subchromosomal domains, presence of cohesins and other chromosome structure proteins, local chromatin structure, and histone modification (Lichten and Goldman 1995;Petes 2001;Kauppi et al 2004;Lichten and de Massy 2011;Pan et al 2011;Acquaviva et al 2013;de Massy 2013;Sommermeyer et al 2013).In some cases, DSB hotspot activity has been shown to depend on the binding of sequence-specific transcription factors (TFs), e.g., at the HIS4 locus in S. cerevisiae and the ade6-M26 allele in Schizosaccharomyces pombe (Schuchert et al 1991;White et al 1991;Kon et al 1997;Steiner et al 2002). However, the role of TFs in shaping genome-wide DSB patterns is complex and poorly defined.…”

MEI4: a central player in the regulation of meiotic DNA double strand break formation in the mouse

“…This finding led to the proposition of a mechanism to tether these sites to the axis (Blat et al, 2002;Panizza et al, 2011). Two recent reports in S. cerevisiae have shown that Spp1 tethers DSB sites to meiotic axes through its direct interaction with Mer2 (Acquaviva et al, 2013;Sommermeyer et al, 2013). In C. elegans, support for a functional link between DSB formation and higher-order chromosome structures is based on the parallel increase of the chromosome axis length and DSB activity in the absence of condensin I (Mets and Meyer, 2009).…”