Lorant Szekvolgyi
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Exploring the SET1 hisonte methylase complex in meiosis: from gene loops to DNA double-strand break (DSB) formation
Initiation of meiotic recombination is impacted by histone H3 methyation that is carried out by the Set1 complex (COMPASS) in budding yeast. Tagging meiotic DSB sites with the broadly localized H3K4me3 mark is a molecular strategy that provides flexibility to ensure transmission of a large diversity of recombinant haplotypes to the offspring. In the current application we aim to find a causative relationship between the presence of the COMPASS subsunit Spp, meiotic DSBs and gene-loop formation upon initiation of meiotic recombination. The current IMERA/INSERM project will be carried out in collaboration with the laboratory of Dr. Vincent Géli. In the planned “biophysical genomics” experiments we will target various histone modifying enzymes and recombinosome proteins to predefined chromosomal loci to induce meiotic recombination in the yeast S cerevisiae. We expect that our results will open new horizons to drill down to the genes to unravel the genetic basis of 3D genome architecture in the context of meiotic recombination.
biographie
Lóránt Székvölgyi’s research lies at the crossroad of molecular biology, biophysics and genetics – for want of better identified as ‘molecular cell biology’. He have been working on the architecture of eukaryotic chromatin focusing on molecular mechanisms that drive DNA recombination events. Since his PhD fellowship (and later as a faculty member of the Dept. of Biophysics and Cell Biology) He has addressed central problems of genome instability: key findings include (1) the discovery of persistent single-stranded DNA breaks in genomic regions that are prone to rearrangements in human malignancies, (2) the discovery of ribonucleoportein particles (RNA-DNA hybrids) in the proximity of these nicks. The latter finding was published in the Proceedings of the National Academy of Sciences of USA, which allowed Lóránt Székvölgyi to establish fruitful collaborations involving leading experts in the field; e.g. Caroline Austin (Newcastle University, UK) who is an expert of topoisomerases and Alain Nicolas (Institut Curie, Paris). A major strand of his work involves molecular knowledge on the developmentally (genetically) programmed DNA double-strand breaks (DSBs): He has been studying DSB formation during the differentiation program of meiosis in S cerevisiae. After 5 years of intense workload, together with the Nicolas group (Paris) and the group of Vincent Géli (Marseille) they found a cause-effect relationship between meiotic DSBs and the presence of an epigenetic tag, H3K4me3. This breakthrough – providing a definitive and unexpected explanation for the link between H3 lysine4 methylation and recombination – was published in Science (as joint-first author with Laurent Acquaviva, CRCM, Marseille) and it was highlighted in Nature Reviews Mol Cell Biol and in Molecular Cell. In 2015 he won the excellence grant of the Hungarian Academy of Sciences, called Momentum, and currently he is the group leader of the MTA-DE Momentum Genome Architecture and Recombination Research Group.
