Gene Regulation: Fred van Leeuwen
Epigenetic regulation of gene expression
In eukaryotic cells the DNA is packaged into chromatin by histone proteins. Post-translational modifications of the histone proteins and methylation of DNA can result in heritable changes in gene expression without changes in the actual genetic code. These epigenetic changes can lead to stable tumor-suppressor gene inactivation or oncogene activation and have been shown to contribute to tumorigenesis. The mechanisms by which epigenetic imprints are established or prevented are still poorly understood. Many chromatin modifiers are conserved from yeast to humans. Our group uses the budding yeast Saccharomyces cerevisiae as a powerful model system to identify new epigenetic regulators and to unravel the molecular mechanisms by which chromatin-modifying enzymes affect chromatin structure and gene expression.
Dot1, an unusual histone methyltransferase controlling the
formation of heterochromatin
We are studying how histones and their post-translational modifications help set up and propagate domains of active and silent chromatin. We recently identified the novel and conserved histone methyltransferase Dot1. This unusual enzyme, which does not have a SET domain, modifies lysine 79 on histone H3 (H3K79) on the top and bottom of the nucleosome core. A common model for histone modifications is that they affect gene activity by locally increasing or decreasing the affinity for regulatory proteins. Our findings are generally consistent with this model, but important issues remain to be resolved. Dot1 enhances silent chromatin formation in yeast but remarkably, H3K79 methylation is very abundant in euchromatin and absent from silent chromatin. We have resolved this paradox by suggesting that H3K79 methylation in euchromatin prevents promiscuous binding of silencing proteins to euchromatin, and thereby enhances their targeting to silent chromatin. This proposes an important interdependence between euchromatin and heterochromatin. We will apply yeast genetics and biochemical methods to reveal the molecular mechanism by which this process occurs and to further explore the role of histone methylation in building and maintaining chromatin domains.
Cellular memory provided by histones and their
One of the main goals of our group is to understand how chromatin modifications can have long-term effects on gene expression. When a cell divides, parental histones (containing their epigenetic marks) and newly synthesized (ground state) histones are somehow assembled onto the daughter DNA strands in a manner that faithfully reproduces the transcriptional states of chromatin that existed prior to chromosome duplication. It is thought that the post-translational modifications on histones can serve as epigenetic memory marks during cell division which eventually act as some kind of template for modifying the new histones. However, the molecular mechanisms by which histone modifications are maintained and contribute to transcriptional memory are unclear. We are developing novel in-vivo assays in yeast to determine how histones and their post-translational modifications are passed on to the daughter cells and help to propagate expression patterns.
In 2010 I started my work as a PhD student in the Van Leeuwen lab. I obtained my bachelor and master degrees in Pharmaceutical Sciences at the VU University. My PhD project revolves around the enzyme Dot1, especially its regulation. I use yeast as a model organism, using both classical yeast genetics and novel screening methods. The knowledge gained from yeast is a good starting point for investigating DOT1L, the human and mouse version of this enzyme. This is the goal of the second part of my project, for which I will use a mouse model and cell lines.
Tibor van Welsem
I started at the NKI in 1998 and worked in different departments. I studied the classification of hereditary breast tumors with genetic profiles obtained by comparative genomic hybridization.
Since 2004 I am working in the laboratory of Fred van Leeuwen. I participate in several projects and provide support to PhD students and postdocs, for example by developing new tools and reagents and by doing genetic screens.
I graduated from a dual-degree program in Bioinformatics at the Free University Amsterdam and Interdisciplinary Medical Sciences at the University at Buffalo. I did my thesis research at Roswell Park Cancer Institute in the lab of Lara Sucheston. I started my PhD at the van Leeuwen lab in 2013. Within my project, I am interested in how the epigenetic landscape of a cell is transmitted. I am approaching this by combining 'wet' and 'dry' lab techniques, with yeast as a model organism.
Deepani Poramba Liyanage
I studied life sciences in Utrecht at the Hogeschool Utrecht with a specialization in zoology. After my first internship at Universiteit Utrecht, working on sexual side effects of SSRI's in mice, I did my final internship at the NKI. At the NKI I did research on PARP inhibitors in BRCA1 deficient mammary tumors in the laboratory of Jos Jonkers. I later returned to the NKI working on different projects involving mouse genetics in the groups of Thijn Brummelkamp and Fred van Leeuwen
Key publications View All Publications
Patterns and mechanisms of ancestral histone protein inheritance in budding yeast
PLoS Biol. 2011;9
Radman-Livaja M, Verzijlbergen KF, Weiner A, van Welsem T, Friedman N, Rando OJ, van Leeuwen FLink to PubMed
Nonprocessive methylation by Dot1 leads to functional redundancy of histone H3K79 methylation states
Nat Struct Mol Biol. 2008;15:550-7
Frederiks F, Tzouros M, Oudgenoeg G, van Welsem T, Fornerod M, Krijgsveld J, van Leeuwen FLink to PubMed
Recent publications View All Publications
Dot1 histone methyltransferases share a distributive mechanism but have highly diverged catalytic properties
Scientific Reports 2015;5
Iris J. E. Stulemeijer, Dirk De Vos, Kirsten van Harten, Onkar K. Joshi, Olga Blomberg, Tibor van Welsem, Marit Terweij, Hanneke...Read more
The emerging roles of DOT1L in leukemia and normal development. Leukemia
McLean CM, Karemaker ID, and Van Leeuwen FLink to PubMed
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