Gene Regulation: Fred van Leeuwen
Histone proteins package eukaryotic genomes and carry post-translational modifications. These modifications affect many transactions of the genome and provide a putative epigenetic memory system to transmit information about genome activity from one cell generation to the next. Epigenetic regulators are frequently mutated in cancer and provide appealing opportunities for therapeutic intervention. The Van Leeuwen lab uses genetic approaches to study mechanisms and principles of epigenetic regulation. Our general strategy is to develop new tools and technologies, taking advantage of yeast as a flexible model system. These novel tools enable us to explore new areas of chromatin biology (e.g. histone dynamics). In addition, they also make it possible to address key questions in the field of epigenetics that have traditionally been difficult to address (e.g. epigenetic memory). Finally, genetic engineering strategies in yeast allow us to dissect specific chromatin processes in high molecular detail (e.g. histone methylation). Our research lines are centered around the two main questions outlined below.
How do epigenetic regulators control genome activity and
how are the regulators regulated?
Following up on our previous discoveries, we focus on the histone methyltransferase Dot1. Dot1 is conserved from yeast to human and involved in human leukemia caused by rearrangements of the MLL1 gene. By combining genetics, quantitative proteomics and mathematical modeling, and by using yeast as an 'in vivo test tube', we recently obtained a high level of mechanistic understanding of Dot1's methylation mechanism. This information has been instrumental for our current studies. By combining novel barcode-sequencing screens (e.g. Epi-ID) and proteomics studies we are unraveling the mechanisms of regulation of Dot1 and its downstream effects on gene expression and cell function. In parallel to our discovery studies in yeast, we have recently started developing tools in human cells using CRISPR-CAS genome editing strategies and mouse models of cancer to translate our findings in yeast to mammals.
What is epigenetic information, how stable is it, how is
To test hypotheses of epigenetic memory, we take advantage of our tools (e.g. Recombination-Induced Tag Exchange or RITE) to measure histone protein inheritance. We also use these tools to study the function and mechanisms of histone protein turnover, a relatively unexplored but most likely very important layer of epigenetic regulation. In addition, we develop screening strategies to uncover the factors involved in histone turnover or inheritance, with the goal to allow functional studies by perturbation.
From time to time we have positions available for PhD students, postdocs, bioinformaticians or technicians. Please send your application and CV to firstname.lastname@example.org if you are interested.
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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