Biomedical genomics

The architecture of DNA in the interior of the living cell nucleus is an emerging key contributor to genomic function. Aim of our research is to understand how genome structure influences genome function. We use and develop novel genomics approaches such as 4C technology to identify long-range DNA interactions, study gene regulation within and between mammalian chromosomes and uncover the proteins that dictate the shape of our genome. Besides transcription we study the impact of nuclear architecture on genomic rearrangements. Furthermore, we develop novel strategies to identify and map chromosomal aberrations.

Wouter de Laat

Wouter de Laat studied biology at the Utrecht University Utrecht. During his PhD (1998) at the Erasmus University Rotterdam (Prof. Jan Hoeijmakers) he investigated the molecular mechanism of nucleotide excision repair. He identified one of the nucleases and characterized the interplay between repair factors at the site of the lesion. As a postdoc, he joined the group of Prof. Frank Grosveld to work on beta-globin gene activation. In 2000 he received a career grant (VIDI) to work on long-range gene activation. His group used 3C technology, and later developed 4C technology, to demonstrate chromatin loops between genes and enhancers and to uncover long-range DNA contacts within and between chromosomes.
In 2008 he received an ERC Young Investigator Grant. In September 2008 de Laat moved his group to the Hubrecht Institute, where he continued his work on genome structure and function. In January 2009 he was appointed professor in Biomedical Genomics at the University Medical Center Utrecht. He received a prestigious VICI career grant in 2012.

Wouter de Laat is founder of -and works one day per week as principal scientist for- Cergentis (www.cergentis.com). Cergentis is a biotech company that provides services and kits for complete gene sequencing based on its proprietary Targeted Locus Amplification (TLA) Technology.

Other activities:
– Scientific board member KWF (Dutch Cancer Society)
– Supervisory board member HUB (Hubrecht Organoid Technology)

w.laat(at)hubrecht.eu

Team members de Laat

Marjon Verstegen

Technician

Marjon Verstegen

Michael van Gerven

student

Michael van Gerven

Carien Hilvering

PhD Student

Catrien

Niels Rinzema

PhD student

Niels Rinzema

Britta Bouwman

PhD Student

Britta Bouwman

Adrien Melquiond

Postdoc

Adrien Melquiond

Christian Valdes

Postdoc

Christian Valdes

Esther Uijttewaal

student

Esther Uijttewaal

Geert Geeven

Postdoc

Geert Geeven

Wouter de Laat

delaat

Erica Vos

PhD Student

Ericabw

Mart van Veldhuizen

Student

Mart van Veldhuizen

Ellen Boele

student

Ellen Boele

Annette Denker

Postdoc

Annette Denker

Carlo Vermeulen

PhD Student

Carlo Vermeulen

Peter Krijger

Postdoc

Peter Krijger

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Research

De Laat: Biomedical genomics

De Laat: Biomedical genomics

The architecture of DNA in the interior of the living cell nucleus is an emerging key contributor to genomic function. Aim of our research is to understand how genome structure influences genome function. We use and develop novel genomics approaches such as 4C technology to identify long-range DNA interactions, study gene regulation within and between mammalian chromosomes and uncover the proteins that dictate the shape of our genome. Besides transcription we study the impact of nuclear architecture on genomic rearrangements. Furthermore, we develop novel strategies to identify and map chromosomal aberrations.

Read research

Key publications

de Vree PJP, de Wit E, Yilmaz M, van de Heijning M, Klous P, Verstegen MJAM, Wan Y, Teunissen H, Krijger PHL, Geeven G, Eijk PP, Sie D, Ylstra B, Hulsman LOM, van Dooren MF, van Zutven LJCM, van den Ouweland A, Verbeek S, van Dijk KW, Cornelissen M, Das AT, Berkhout B, Sikkema-Raddatz B, van den Berg E, van der Vlies P, Weening D, den Dunnen JT, Matusiak M, Lamkanfi M,  Ligtenberg MJL, ter Brugge P, Jonkers J, Foekens JA, Martens JW, van der Luijt R, Ploos van Amstel HK, van  Min M, Splinter E, de Laat W (2014). Targeted sequencing by proximity ligation for comprehensive variant detection and local haplotyping. Nature Biotechnology 32(10):1019-25.

de Laat W, Duboule D (2013). Topology of mammalian developmental enhancers and their regulatory landscapes. Nature 502(7472):499-506.

de Wit E, Bouwman BA, Zhu Y, Klous P, Splinter E, Verstegen MJ, Krijger PH, Festuccia N, Nora EP, Welling M, Heard E, Geijsen N, Poot RA, Chambers I, de Laat W. (2013) The pluripotent genome in three dimensions is shaped around pluripotency factors. Nature 501(7466):227-31.

van de Werken H, Landan G, Holwerda S, Hoichman M, Klous P, Chachik R, Splinter E, Valdes Quezada C, Öz Y, Bouwman B, Verstegen M, de Wit E, Tanay A, de Laat W. (2012). Robust 4C-seq data analysis to screen for regulatory DNA interactions. Nature Methods 9:969-72.

Noordermeer D#, de Wit E#, Klous P#, van de Werken H, Simonis M, Lopez-Jones M, Eussen B, de Klein A, Singer RH, de Laat W. (2011). Variegated gene expression caused by cell-specific long-range DNA interactions. Nat Cell Biol 13:944-51.
#equal contributions

All publications

Genome-wide profiling of p53-regulated enhancer RNAs uncovers a subset of enhancers controlled by a lncRNA
2015

Nicolas Léveillé, Carlos A Melo, Koos Rooijers, Angel Díaz-Lagares, Sonia A Melo, Gozde Korkmaz, Rui Lopes, Farhad Akbari Moqadam, Ana R Maia, Patrick J Wijchers, Geert Geeven, Monique L den Boer, Raghu Kalluri, Wouter de Laat, Manel Esteller, Reuven Agami

Architectural hallmarks of the pluripotent genome
2015

Britta A M Bouwman, Wouter de Laat

Characterization and dynamics of pericentromere-associated domains in mice
2015

Patrick J Wijchers, Geert Geeven, Michael Eyres, Atze J Bergsma, Mark Janssen, Marjon Verstegen, Yun Zhu, Yori Schell, Carlo Vermeulen, Elzo de Wit, Wouter de Laat

Getting the genome in shape
2015

Britta Am Bouwman, Wouter de Laat

Dynamics of gene silencing during X inactivation using allele-specific RNA-seq
2015

Hendrik Marks, Hindrik H D Kerstens, Tahsin Stefan Barakat, Erik Splinter, René A M Dirks, Guido van Mierlo, Onkar Joshi, Shuang-Yin Wang, Tomas Babak, Cornelis A Albers, Tüzer Kalkan, Austin Smith, Alice Jouneau, Wouter de Laat, Joost Gribnau, Hendrik G Stunnenberg

CTCF Binding Polarity Determines Chromatin Looping
2015

Elzo de Wit, Erica S M Vos, Sjoerd J B Holwerda, Christian Valdes-Quezada, Marjon J A M Verstegen, Hans Teunissen, Erik Splinter, Patrick J Wijchers, Peter H L Krijger, Wouter de Laat

YAP Drives Growth by Controlling Transcriptional Pause Release from Dynamic Enhancers
2015

Giorgio G Galli, Matteo Carrara, Wei-Chien Yuan, Christian Valdes-Quezada, Basanta Gurung, Brian Pepe-Mooney, Tinghu Zhang, Geert Geeven, Nathanael S Gray, Wouter de Laat, Raffaele A Calogero, Fernando D Camargo

High-Affinity Sites Form an Interaction Network to Facilitate Spreading of the MSL Complex across the X Chromosome in Drosophila
2015

Fidel Ramírez, Thomas Lingg, Sarah Toscano, Kin Chung Lam, Plamen Georgiev, Ho-Ryun Chung, Bryan R Lajoie, Elzo de Wit, Ye Zhan, Wouter de Laat, Job Dekker, Thomas Manke, Asifa Akhtar

A Long-Distance Chromatin Affair
2015

Annette Denker, Wouter de Laat

Local compartment changes and regulatory landscape alterations in histone H1-depleted cells
2015

Geert Geeven, Yun Zhu, Byung Ju Kim, Boris A Bartholdy, Seung-Min Yang, Todd S Macfarlan, Wesley D Gifford, Samuel L Pfaff, Marjon J A M Verstegen, Hugo Pinto, Marit W Vermunt, Menno P Creyghton, Patrick J Wijchers, John A Stamatoyannopoulos, Arthur I Skoultchi, Wouter de Laat

Transcription of Mammalian cis-Regulatory Elements Is Restrained by Actively Enforced Early Termination
2015

Liv M I Austenaa, Iros Barozzi, Marta Simonatto, Silvia Masella, Giulia Della Chiara, Serena Ghisletti, Alessia Curina, Elzo de Wit, Britta A M Bouwman, Stefano de Pretis, Viviana Piccolo, Alberto Termanini, Elena Prosperini, Mattia Pelizzola, Wouter de Laat, Gioacchino Natoli

Quantitative analysis of chromatin interaction changes upon a 4.3 Mb deletion at mouse 4E2
2015

Cinthya J Zepeda-Mendoza, Swagatam Mukhopadhyay, Emily S Wong, Nathalie Harder, Erik Splinter, Elzo de Wit, Melanie A Eckersley-Maslin, Thomas Ried, Roland Eils, Karl Rohr, Alea Mills, Wouter de Laat, Paul Flicek, Anirvan M Sengupta, David L Spector

Targeted sequencing by proximity ligation for comprehensive variant detection and local haplotyping
2014

Paula J P de Vree, Elzo de Wit, Mehmet Yilmaz, Monique van de Heijning, Petra Klous, Marjon J A M Verstegen, Yi Wan, Hans Teunissen, Peter H L Krijger, Geert Geeven, Paul P Eijk, Daoud Sie, Bauke Ylstra, Lorette O M Hulsman, Marieke F van Dooren, Laura J C M van Zutven, Ans van den Ouweland, Sjef Verbeek, Ko Willems van Dijk, Marion Cornelissen, Atze T Das, Ben Berkhout, Birgit Sikkema-Raddatz, Eva van den Berg, Pieter van der Vlies, Desiree Weening, Johan T den Dunnen, Magdalena Matusiak, Mohamed Lamkanfi, Marjolijn J L Ligtenberg, Petra ter Brugge, Jos Jonkers, John A Foekens, John W Martens, Rob van der Luijt, Hans Kristian Ploos van Amstel, Max van Min, Erik Splinter, Wouter de Laat

A large permissive regulatory domain exclusively controls Tbx3 expression in the cardiac conduction system
2014

Jan Hendrik van Weerd, Ileana Badi, Malou van den Boogaard, Sonia Stefanovic, Harmen J G van de Werken, Melisa Gomez-Velazquez, Claudio Badia-Careaga, Miguel Manzanares, Wouter de Laat, Phil Barnett, Vincent M Christoffels

A single oncogenic enhancer rearrangement causes concomitant EVI1 and GATA2 deregulation in leukemia
2014

Stefan Gröschel, Mathijs A Sanders, Remco Hoogenboezem, Elzo de Wit, Britta A M Bouwman, Claudia Erpelinck, Vincent H J van der Velden, Marije Havermans, Roberto Avellino, Kirsten van Lom, Elwin J Rombouts, Mark van Duin, Konstanze Döhner, H Berna Beverloo, James E Bradner, Hartmut Döhner, Bob Löwenberg, Peter J M Valk, Eric M J Bindels, Wouter de Laat, Ruud Delwel

A common genetic variant within SCN10A modulates cardiac SCN5A expression
2014

Malou van den Boogaard, Scott Smemo, Ozanna Burnicka-Turek, David E Arnolds, Harmen J G van de Werken, Petra Klous, David McKean, Jochen D Muehlschlegel, Julia Moosmann, Okan Toka, Xinan H Yang, Tamara T Koopmann, Michiel E Adriaens, Connie R Bezzina, Wouter de Laat, Christine Seidman, J G Seidman, Vincent M Christoffels, Marcelo A Nobrega, Phil Barnett, Ivan P Moskowitz

Flexible long-range loops in the VH gene region of the Igh locus facilitate the generation of a diverse antibody repertoire
2013

J. Medvedovic, A. Ebert, H. Tagoh, I.M. Tamir, T.A. Schwickert, M. Novatchkova, Q. Sun, P.J. Huis In 't Veld, C. Guo, H.S. Yoon, Y. Denizot, S.J. Holwerda, W. de Laat, M. Cogne, Y. Shi, F.W. Alt, M. Busslinger

Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells
2013

S.J. Holwerda, H.J. van de Werken, C. Ribeiro de Almeida, I.M. Bergen, M.J. de Bruijn, M.J. Verstegen, M. Simonis, E. Splinter, P.J. Wijchers, R.W. Hendriks, W. de Laat

eRNAs are required for p53-dependent enhancer activity and gene transcription
2013

C.A. Melo, J. Drost, P.J. Wijchers, H. van de Werken, E. de Wit, J.A. Oude Vrielink, R. Elkon, S.A. Melo, N. Leveille, R. Kalluri, W. de Laat, R. Agami

The pluripotent genome in three dimensions is shaped around pluripotency factors
2013

E. de Wit, B.A.M. Bouwman, Y. Zhu, P. Klous, E. Splinter, M.J. Verstegen, P.H. Krijger, N. Festuccia, E.P. Nora, M. Welling, E. Heard, N. Geijsen, R.A. Poot, I. Chambers, W. de Laat