Chromosome structure and dynamics
Figure 1: Model for the organisation of mitotic chromosomes by condensin rings
Figure 2: Monitoring chromosome structure and segregation in fission yeast cells
The Häring group aims to understand the molecular machinery that organises chromosomes to allow their correct distribution among daughter cells.
Previous and current research
Eukaryotic chromosomes undergo enormous changes in structure and organisation over the course of a cell cycle. One of the most fascinating changes is the transformation of interphase chromatin into rod-shaped mitotic chromosomes in preparation for cell division. This process, known as chromosome condensation, is a key step for the successful segregation of chromosomes during mitosis and meiosis. However, the underlying mechanisms are still poorly understood.
The overall aim of our research is to unravel the action of molecular machines that organise the 3D arrangement of chromosome fibres. Insights into the general working principles behind these machines will be of great importance to our understanding of how cells inherit a complete set of their genomes every time they divide and prevent the occurrence of aneuploidies, which are hallmarks of most cancer cells and the leading cause of spontaneous miscarriages in humans.
One of the central players in the formation of mitotic chromosomes is a highly conserved multi-subunit protein complex, known as condensin. We have shown that condensin binds to mitotic chromosomes by encircling chromosomal DNA within a large ring structure formed by its structural maintenance of chromosomes (SMC) and kleisin subunits. Our working hypothesis is that condensin uses this topological principle to tie together loops of chromatin and thereby maintain mitotic chromosomes in their characteristic shape (figure 1).
In an independent project, we have started the search for additional players that direct the formation of mitotic and meiotic chromosomes. We have developed a timeresolved light microscopy assay that allows us to quantitatively measure chromosome condensation in live fission yeast cells in high throughput (figure 2).
Future projects and goals
We are using an interdisciplinary approach to advance our understanding of condensin function in yeast and mammalian cells by combining biochemical, molecular, and cell biological methods. In collaboration with other groups, we are taking further advantage of structural and chemical biological as well as biophysical techniques to discover how condensin loads onto chromosomes, how it interacts with other chromosomal components, and how its activity is controlled.
Using the live-cell chromosome condensation assay, we are now screening large pools of fission yeast mutants to identify novel components of the chromosome condensation machinery. With the first candidates in hand, we will investigate the bases of their functions on mitotic chromosomes using the full repertoire of cellular and molecular biology.