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Gene Regulation: Fred van Leeuwen

FredVanLeeuwen.jpg

Fred van Leeuwen, Ph.DGroup leader

About Fred van Leeuwen

Research interest

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 it transmitted?
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.

Available positions
From time to time we have positions available for PhD students, postdocs, bioinformaticians or technicians. Please send your application and CV to fred.v.leeuwen@nki.nl if you are interested.

Co-workers

Vlaming, Hanneke

Hanneke Vlaming

PhD student

Experience

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.

 

 

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Welsem, Tibor van.jpg

Tibor van Welsem

Technician

Experience

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. 

 

 

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Korthout, Tessa.JPG

Tessy Korthout

PhD student

Experience

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.

 

 

 

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Maliepaard, Eliza Marie

Eliza Mari Maliepaard

PhD student

Experience

I obtained both my bachelor and master degree in Biomedical Sciences at the Radboud University in Nijmegen. During my master I performed two research internships in the fields of epigenetics and cancer. I started my PhD at the van Leeuwen group in 2016.

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Poramba Liyanage, Deepani.JPG

Deepani Poramba Liyanage

PhD Student

Experience

 

 

 

 

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Thom Molenaar nieuw

Thom Molenaar

PhD student

Experience

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Morais D

Morais, Dominique

undergraduate student

Experience

I am currently a student of the University of Applied science at Hogeschool Leiden. In April 2016 I joined the van Leeuwen lab for both my minor and major internship.

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Pages, Marco

Marc Pages Gallego

Master student

Experience

I graduated in biotechnology at the Rovira I Virgili University (URV) in Catalonia, during that period I did 2 internships at the Helmholtz Centre for Environmental Research (UFZ) in Leipzig and the Polytechnic University of Catalonia (UPC). Afterwards, I started my master's in bioinformatics and systems biology at the Universiteit van Amsterdam (UvA). I am currently doing my first master's internship at the Netherlands Cancer Institute (NKI) in the Gene Regulation research group. Here I develop tools to measure histone H3.3 turnover to uncover the underlying mechanisms of histone recycling.

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Kruijbergen, van Ilja

Ila van Kruijsbergen

Postdoc

Experience

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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 F

    Link 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 F

    Link 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

    Leukemia: 2014

    McLean CM, Karemaker ID, and Van Leeuwen F

    Link to PubMed
 

Contact

  • Office manager

    Suzanne Corsetto

  • E-mail

    s.corsetto@nki.nl

  • Telephone Number

    + 31 20 512 1970

Suzanne Corsetto

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