How is DNA folded inside the cell nucleus? How is DNA packaged
by hundreds of chromatin proteins? And how do DNA folding and
packaging regulate gene expression? These fascinating questions are
of fundamental interest and highly relevant to our understanding of
cancer and other diseases. Our attempts to solve these questions by
developing new genomics techniques that can provide new views of
the spatial organization of DNA, and how chromatin proteins work
together to package and regulate the genome.
The human genome is a four-dimensional map of our
body. It contains instructions where and when in our body a gene or
protein needs to be expressed. Charting the spatio-temporal aspects
of gene expression is one of the great challenges in systems
biology. My group is interested in on the one hand identifying
regulatory mutations that affect gene expression. On the other hand
we want to understand the role genome storage plays in the
regulation of genes.
Beginning his scientific career at the NKI working on African
trypanosomes, Fred van Leeuwen developed an interest in epigenetics
- the process by which genes are stably switched on or off - and he
returned in 2003 to establish his own research group on the topic.
Although an identical set of genes is found in every cell in the
body they are not all in the same on or off state, which allows
each cell to function differently. These patterns of gene activity
are also passed on to future cell generations. Fred's group is
interested in how cells maintain their identity and pass on this
memory of gene activity to daughter cells through cell division,
which can lead to insights into the development of cancer.
Our lab is interested in understanding the mechanisms of
transcription regulation in eukaryotic cells. In the last half
century, our knowledge of gene expression has greatly advanced, but
the majority of measurements come from large populations of cells.
However, as a result of the stochastic nature of transcriptional
process itself, cells can exhibit considerable heterogeneity in
transcriptional responses. This stochastic gene expression
variation can influence essential cell fate decisions, such as the
decision to go into apoptosis. Diseases such as cancer often start
when individual cells start acting aberrantly, illustrating the
importance of single-cell approaches to study biological
Human chromosomes are centimetres in length, but are organized
such that they fit into a cell of micrometre-scale dimensions.
Within this confined setting, chromosomes allow for tightly
controlled cellular processes such as mitosis and transcription.
These processes are to an important degree made possible by two
conserved protein complexes known as cohesin and condensin. Both
cohesin and condensin are so-called SMC complexes that by
entrapping DNA inside their ring-shaped lumens can structure
chromosomes. Our research centres on the mode of action of these
vital protein complexes.