Laboratory Marieke Oudelaar
Genome Biology
The Oudelaar lab investigates the interplay between the 3D organization of the genome and the regulation of gene expression using cutting-edge technologies to analyze genome folding and gene regulation across scales and biological contexts.
We investigate the interplay between the 3D organization of the genome and the regulation of gene expression. To this end, we develop and apply cutting-edge technologies to analyze genome folding and gene regulation across scales and biological contexts. By integrating genomics, imaging, proteomics, biochemistry, and computational biology, we take an interdisciplinary approach to define the organizational principles of the 3D genome and determine how 3D genome structures contribute to precise regulation of gene expression during cellular differentiation and development.
Mission
A fundamental question in biology is how one genome (one DNA sequence) can give rise to the remarkable diversity of cell types that make up multicellular organisms. Distinct cellular states reflect specific gene expression programs, which are controlled by regulatory elements in the genome. Among these, enhancers and promoters play key roles in determining when, where, and at what level genes are expressed. While promoters are usually located near the genes they control, enhancers can act over hundreds of kilobases and often bypass nearby genes to regulate distant target genes.
The spatial organization of the genome within the nucleus is important for accurate communication between enhancers and promoters. These elements interact within 3D genome structures, allowing regulatory regions that are separated by large genomic distances to come into functional contact. Specific enhancer–promoter interactions are critical for establishing accurate gene expression programs during differentiation and development. Perturbations of this process have been linked to congenital disorders and human cancers. However, the fundamental principles governing the formation, specificity, and function of these regulatory interactions remain incompletely understood.
Goals
Our goals are to (1) define the 3D organization of eukaryotic genomes at high resolution across scales and biological contexts; (2) identify the molecular mechanisms that drive the formation of 3D genome structures; and (3) determine how gene expression is regulated within this 3D nuclear environment.
Approach
We take an interdisciplinary approach to study 3D genome organization and gene regulation. We develop and apply high-resolution genomics and imaging technologies to analyze genome organization and gene regulation across scales and biological contexts. In parallel, we use bottom-up biochemical approaches to reconstitute key features of 3D genome folding and directly dissect the molecular mechanisms involved. We integrate these experimental strategies with computational approaches, drawing on concepts from molecular dynamics and polymer physics, to develop a holistic understanding of 3D genome organization and gene regulation.
Impact
In-depth understanding of 3D genome organization and gene regulation is not only central to fundamental biology, but also increasingly important for interpreting genomic data from large-scale human genetics and cancer genomics studies. Many disease-associated genetic variants lie in non-coding regulatory regions of the genome, where their target genes and mechanisms of action are often unclear. Interpreting these variants requires a detailed understanding of how regulatory elements control gene expression within the 3D nuclear environment. Ultimately, this knowledge can help elucidate disease mechanisms at the molecular level and provide a foundation for future advances in diagnosis and treatment.