de Laat: Biomedical genomics

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The De Laat group studies genome structure and function in development and disease and develops DNA sequencing methods for improved clinical diagnostics.

Nuclear organisation and gene expression

The mammalian genome contains millions of non-coding sequences with transcriptional regulatory potential, including enhancers, which can activate gene expression, and insulators, which can block enhancer action. A main interest of our work is to understand how this dizzying array of regulatory sequences is functionally wired to the roughly twenty thousand genes present, such that the orchestration of gene expression is properly executed in both time and place, and how faulty wiring of these elements leads to disease.

Thanks to the work of many researchers, including those from our own group, the shape of the genome is now appreciated as an important contributor to transcriptional control. Chromosome conformation capture (3C) technologies in particular have greatly contributed to this understanding and have uncovered a hierarchical organization of genome topology that is intimately linked to the regulation of gene expression. Enhancers act on (distal) target genes via 3D chromatin looping. They function in the spatial context of structural domains or ’topologically associating domains’ (TADs), which are believed to demarcate microenvironments for genes and regulatory elements to roam within and to make productive DNA contacts. In the larger nuclear space, TADs segregate and cluster into active (A) and inactive (B) compartments that can each be further divided into nuclear sub-compartments with distinct chromatin signatures.

Hierarchical 3D genome organisation, showing chromosome territories (left), nuclear A and B compartments, TADs and and sub-TADs (middle panel) and chromatin loops (right panels). Adapted from Denker and de Laat, Genes Dev 2016.

The aim of our research is to deepen our understanding of the relationship between genome structure and function in mammalian cells, in health and in disease.

Techniques

We use and develop novel genomics approaches and computational tools that employ Next Generation Sequencing and Oxford Nanopore Single Molecule Sequencing (a) to accelerate progress in our understanding of the 3D genome and its impact on gene regulation and (b) for improved DNA diagnostics in the clinic. As an illustration:

We were the first to adapt 3C technology to study enhancer-promoter interactions (Tolhuis, 2002)
We developed 4C technology (Simonis, 2006)
We developed high-resolution 4C technology for detailed DNA contact studies focused on genes and regulatory sequences (van de Werken, 2013)
We demonstrated that ‘C’ technologies can be employed as diagnostic tools, for the detection of chromosomal rearrangements (Simonis, 2009)
Together with our spin-off company Cergentis we developed Targeted Locus Amplification (TLA technology: de Vree, 2014)
We developed multi-contact 4C (Allahyar, 2017)

Strategy for Monogenic Non-Invasive Prenatal Diagnosis. A. Summary of the MG-NIPD approach. Blood is isolated from both parents and cells are used to TLA haplotype the disease locus. Cell-free DNA is isolated from maternal plasma during pregnancy and sequenced to analyze cell-free fetal DNA. Parental locus-specific haplotypes are used to discern which combination of parental alleles is overrepresented in cell-free DNA and therefore inherited by the fetus. B. Targeted haplotyping by TLA. Crosslinking (blue ovals), digestion and proximity ligation primarily yields intra-chromosomal ligation products. Ligation products containing a (viewpoint) SNP of interest (yellow and green triangles) can be selectively amplified by inverse PCR and sequenced. Variants ending up in the same ligation product (indicated respectively by blue and red triangles) are assigned to the same allele (phasing).

Our previous work

Most of our research has been dedicated to understanding gene regulation in development and disease (e.g. cancer) and how this is controlled by non-coding regulatory DNA elements that often lie away from genes on the linear chromosome. In our earlier work, we were the first to adapt 3C technology to study DNA topology in mammals and demonstrate that distant enhancers and promoters contact each other for gene regulation (Tolhuis, Mol Cell 2002; Palstra, Nat Genetics 2003). We also provided first evidence that transcription factors mediate chromatin loops (Drissen, Genes and Dev 2004). In 2006 we were the first to demonstrate that CTCF forms chromatin loops (Splinter, Genes and Dev 2006) and we published our now widely used 4C technology (Simonis, Nat Genetics 2006).

Key publicationsView all publications

Building regulatory landscapes reveals that an enhancer can recruit cohesin to create contact domains, engage CTCF sites and activate distant genes

Rinzema NJ, Sofiados k, [...], de Laat W

Nature Structural & Molecular Biology (2022)

Download|2022

Ready-to-use public infrastructure for global SARS-CoV-2 monitoring

Krijger PHL, Hoek TA, [...], de Laat W, Tanenbaum M

Nature Biotechnology 39: 1178–1184

Download|2021

Interplay between CTCF boundaries and a super enhancer controls cohesin extrusion trajectories and gene expression

Vos ESM, Valdes-Quezada C, Huang Y [...], de Laat W

Mol. Cell 81(15):3082-3095

Download|2021

Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing

Allahyar A, Pieterse M, [...], de Laat W

NATURE COMMUNICATIONS: 12:3361

Download|2021

Novel orthogonal methods to uncover the complexity and diversity of nuclear architecture

Tjalsma SJD, de Laat W

Current Opinion in Genetics & Development: 67:10-17

Download|2021

How chromosome topologies get their shape: views from proximity ligation and microscopy methods

Huang Y, Neijts R, de Laat W

FEBS Letters: 594 3439–3449

Download|2020

Multi-contact 4C: long-molecule sequencing of complex proximity ligation products to uncover local cooperative and competitive chromatin topologies

Vermeulen C, Allahyar A [...], de Ridder J, de Laat W

Nat Protocols;15(2):364-397

Download|2020

4C-seq from beginning to end: A detailed protocol for sample preparation and data analysis

Krijger PHL, Geeven G, [...], de Laat W

Methods: 170 17–32

Download|2019

DamC reveals principles of chromatin folding in vivo without crosslinking and ligation

Redolfi J, Zhan Y, Valdes-Quezada C, [...], de Laat W, Giorgetti L

Nat Struct Mol Biol. ; 26(6): 471–480

Download|2019

Enhancer hubs and loop collisions identified from single-allele topologies

Allahyar A, Vermeulen C, [...], de Ridder J, de Laat W

Nature Genetics 50:1151–1160

Download|2018

Sensitive Monogenic Noninvasive Prenatal Diagnosis by Targeted Haplotyping.

Vermeulen C, Geeven G, [...], de Laat W

American Journal of Human Genetics 101,1-14.

Download|2017

Cell-of-origin specific 3D genome structure acquired during somatic cell reprogramming.

Krijger PHL, Di Stefano B, [...], de Laat W, Graf T

Cell Stem Cell, 18(5):597-610.

Download|2016

Cause and consequence of tethering a sub-TAD to different nuclear compartments.

Wijchers PJ, Krijger PHL, [...], de Laat W

Molecular Cell, 61(3):461-73.

Download|2016

CTCF binding polarity determines chromatin looping.

de Wit E, Vos ESM, [...], de Laat W

Mol. Cell. 60(4):676-84.

Download|2015

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

de Vree PJP, de Wit E, [...], de Laat W

Nature Biotechnology 32(10):1019-25.

Download|2014

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

de Wit E, Bouwman BA, [...], de Laat W

Nature 501(7466):227-31.

Download|2013

Robust 4C-seq data analysis to screen for regulatory DNA interactions.

van de Werken H, Landan G, [...], de Laat W

Nature Methods, 9:969-72.

Download|2012

High-resolution identification of balanced and complex chromosomal rearrangements by 4C technology.

Simonis M, Klous P, [...], de Laat W

Nature Methods 6:837-42.

Download|2009

CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus.

Splinter E, Heath H, [...], de Laat W

Genes & Dev 20: 2349-2354.

Download|2006

Nuclear organization of active and inactive chromatin domains uncovered by chromosome conformation capture-on-chip (4C).

Simonis M, Klous P, [...], de Laat W

Nature Genetics 38:1348-1354.

Download|2006

The beta-globin nuclear compartment in development and erythroid differentiation.

Palstra RJ, Tolhuis B, Splinter E, Nijmeijer R, Grosveld F, de Laat W

Nature Genetics 35, 190-194.

Download|2003

Looping and interaction between hypersensitive sites in the active beta-globin locus.

Tolhuis B, Palstra RJ, Splinter E, Grosveld F, de Laat W

Molecular Cell 10: 1453–1465,

Download|2002

Group leader

Wouter de Laat

Wouter de Laat is group leader at the Hubrecht Institute, Investigator at Oncode Institute and professor of Biomedical Genomics at University Medical Center Utrecht. His research focuses on two main themes, with a strong emphasis on technology development. One focus is on epigenetics and gene expression; in particular, how the 3D architecture of the genome impacts on transcription regulation. By developing and applying innovative high-throughput technologies he and his team aim to accelerate progress in understanding genome structure-function relationships. The second focus is on clinical diagnostics. His research group develops DNA sequencing technologies for clinical applications, for example for optimized oncogenetic diagnostics and for non-invasive prenatal diagnosis of monogenic diseases.

Scientific training and positions