Image: Mattias Pettersson
Research group All cells of our bodies have the same genes. Yet only some of them are used in any given cell type. So-called epigenetic mechanisms ensure that genes, which were not selected to be active, remain silent. We employ Drosophila and human cell culture models, genomics, genetics and numerical simulations to understand molecular mechanisms of epigenetic regulation by Polycomb and Trithorax proteins.
Group Yuri Schwartz.
ImageMattias PetterssonExploring chromatin dynamics of epigenetically repressed genes with TRIP.
Epigenetic repression of developmental genes by the Polycomb group proteins involves methylation of histone H3 at lysine 27 (H3K27). This covalent modification serves as a molecular mark, ensuring that both copies of a target gene remain repressed after DNA replication. An important open question is how the H3K27 methylation mark helps to facilitate epigenetic repression. A recent study from our group showed that stochastic interactions of PRE-tethered PRC1 with H3K27me3 are sufficient to fold the methylated chromatin. However, the resulting chromatin folding is too modest (no more than 2-fold on average) to be an obvious obstacle for transcription. Computational modelling suggests that interactions of PRE-bound PRC1 with the surrounding H3K27me3 slow down the transitions of the chromatin fibre from one folding conformation to another. If transcription initiation happens only in certain infrequent folding conformations, reduced chromatin fibre dynamics will inhibit the process. We employ the Thousands of Reporters Integrated in Parallel (TRIP) approach to study the effect of PRC1-H3K27me3 interactions on chromatin dynamics.
Beyond the histone code: searching for non-histone targets of Trithorax group methylases.
Mutations in genes encoding Trithorax (Trx) and Ash1 proteins cause excessive Polycomb repression, severe developmental abnormalities and, in mammals, have been linked to multiple forms of cancer. In vitro, both Trx and Ash1 can methylate specific Lysines within histone H3. However, histone replacement experiments indicate that methylation of histone H3 is not how Ash1 or Trx stop Polycomb repression. To understand the true mechanism we need to discover other proteins methylated by Ash1 and Trx. We aim to do this by combining biochemical approaches with the power of Drosophila genetics.
Molecular biology of MLL1-driven leukaemia.
Chromosomal rearrangements involving the human Mixed Lineage Leukaemia 1 gene (MLL1 a.k.a. MLL or KMT2A) are found in approximately 10% of acute myeloid leukaemia (AML) in adults, 2%-5% of paediatric acute lymphoblastic leukaemia (ALL), and are predominant (>70%) in infant ALL. Commonly, such rearrangements are balanced translocations that fuse MLL1 with another gene, creating two novel fusion proteins containing N- and C-terminal parts of MLL1. Extensive studies of the last two decades revealed that MLL1 is a histone methyltransferase and that some of its oncogenic fusions are chromatin-associated proteins. However, molecular mechanisms linking MLL1 to oncogenic transformation remain unclear. Does MLL1, like its Drosophila ortholog Trx, act by limiting epigenetic repression of developmental genes? Do oncogenic fusions perturb epigenetic repression of alternative gene expression programs? Is the MLL1 methyltransferase activity critical for its oncogenic function, and what are the relevant substrates? Addressing these questions is another research interest of our laboratory.
Lundkvist MJ, Lizana L, Schwartz YB. 2023. Forecasting histone methylation by Polycomb complexes with minute-scale precision. Science Advances. 9:eadj8198. doi: 10.1126/sciadv.adj8198.
Barrasa JI, Kahn TG, Lundkvist MJ, Schwartz YB. 2023. DNA elements tether canonical Polycomb Repressive Complex 1 to human genes. Nucleic Acids Res. 51:11613-11633. doi: 10.1093/nar/gkad889.
Lizana L, Nahali N, Schwartz YB. 2023. Polycomb proteins translate histone methylation to chromatin folding. J Biol Chem 299:105080. doi.org/10.1016/j.jbc.2023.105080
Kahn TG, Savitsky M, Kuong C, Jacquier C, Cavalli G, Chang JM, Schwartz YB. 2023. Topological screen identifies hundreds of Cp190- and CTCF-dependent Drosophila chromatin insulator elements. Science Advances 9:eade0090. doi: 10.1126/sciadv.ade0090.
Dorafshan E, Kahn TG, Glotov A, Savitsky M, Walther M, Reuter G, Schwartz YB. 2019. Ash1 counteracts Polycomb repression independent of histone H3 Lysine 36 methylation. EMBO Rep 20: e46762. doi: 10.15252/embr.201846762.
Kahn TG, Dorafshan E, Schultheis D, Zare A, Stenberg P, Reim I, Pirrotta V, Schwartz YB. 2016. Interdependence of PRC1 and PRC2 for recruitment to Polycomb Response Elements. Nucleic Acids Res. 44:10132-10149. doi: 10.1093/nar/gkw701.
