Figure 1: Model for the organisation of mitotic chromosomes by condensin rings.
Figure 2: The live-cell chromosome condensation assay tracks the distances between two fluorescently labelled chromosome loci over time. Alignment of a large number of single cell tracks (circles) to the time of anaphase onset (t = 0) generates an average distance plot (line) as a quantitative read-out of condensation dynamics.
The Häring group aims to understand the molecular machinery that organises mitotic chromosomes.
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. The underlying mechanisms are, however, still poorly understood.
The overall aim of our research is to unravel the action of molecular machines that organise the 3D architecture of eukaryotic genomes. 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 chromosomes every time they divide and thereby prevent the emergence 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 encircles 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 (figure 1), which ensures that chromosome arms clear the site of cell cleavage before cytokinesis.
In an independent project, we use a newly developed time-resolved light microscopy assay to quantitatively measure chromosome condensation in live fission yeast cells in high-throughput (figure 2). This has identified, in addition to condensin, new players that direct the formation of mitotic and meiotic chromosomes.
Future projects and goals
We will continue to use a highly interdisciplinary approach to advance our understanding of condensin function in yeast and mammalian cells by combining biochemical, molecular, structural, and cell biology methods. In collaboration with other groups, we are taking further advantage of chemical biological techniques as well as single-molecule approaches to discover how condensin loads onto chromosomes, how it interacts with other chromosomal components, and how its activity is controlled. In addition, we are further investigating the novel candidates identified in the screen for mitotic chromosome condensation proteins to understand the basis of their functions on mitotic chromosomes.