All living organisms store their genetic information on chromosomal fibers — extremely long, flexible molecules, tightly packed into a tiny space inside the cell. To read, duplicate and pass this information to their progeny, cells must constantly fold and re-fold chromosomes. Errors in this essential process can interfere with the basic functions of reading and reproduction, and lead to disease. Our group studies the three-dimensional structure of genomes, the mechanisms by which cells modify the structure and the role this structure plays in cell function. To do this, we approach biological questions with theoretical methods of statistical physics, computer simulations, and computational biology.
Our group seeks to answer fundamental questions of genome biology that arise from these tightly packed, exquisitely organized chromosomes. We are interested in how cells first pack, and then segregate their genomes during cell division. We want to understand how cells bring regulatory sequences and their targets together in space, and how they find pairs of DNA segments with similar sequences for recombination. We also look at the challenges posed by the polymer nature of genomes for maintenance and repair.
We are a “dry lab” - we address biological questions using theoretical research methods of physics and computer science rather than traditional “wet” experiments at the lab bench. We apply a very broad range of these “dry” methods to build physical models of the genome, process and interpret massive amounts of biological data and draw biological conclusions.
Studying genome structures is difficult in part because they vary greatly from cell to cell and over time. In that sense, the genome does not have a single dominant structure but can assume a whole ensemble of different structures. We use the language and ideas of polymer physics to describe these ensembles and build physical models of genomes. Such models let us predict how likely different genome structures are to occur inside living cells, how these structures can change over time and how they are affected by various mechanisms that cells employ to organize their genomes.
One of the most exciting recent discoveries in our field is that genomes are shaped by “loop extruding” enzymes. These enzymes can bind to DNA and reel it in, thus forming loops and compacting chromosomes. Our group wants to get a quantitative understanding of this process, i.e. what kinds of loop structures can be formed by this process, and how the resulting structures depend on the parameters of motor enzymes and various factors affecting their function. We model the process of loop extrusion using lattice models, which model chromosomes as an array of sites that can be occupied by moving enzymes. These models help us understand how many motor enzymes, each acting independently according to a few simple rules, together can self-organize into beautiful structures with non-trivial properties.
Modern biological experiments generate massive amounts of sequencing data and thus rely heavily on high-performance computations and advanced statistics. Our field of 3D genomics is at the forefront of this development: chromosome conformation capture (Hi-C) experiments produce terrabytes of data, which are difficult to interpret both conceptually and practically. Our group develops new approaches to the analysis of Hi-C data. We leverage our understanding of the polymer nature of genomes to invent new algorithms for the interpretation of Hi-C data. We also develop and maintain open-source programming tools for easy and efficient processing of large volumes of Hi-C data.
While we rely on methods of computer science and physics, our research agenda focuses on the fundamental questions in cell biology. This style of research critically depends on tight collaboration with experimental biology labs. We find these collaborations to be truly satisfying and synergistic. While we provide our expertise in advanced topics of computations and physics, in return, we get a chance to test and refine our models, find new research questions, and identify the most impactful directions for future software development. Vienna BioCenter provides a fantastic environment for our style of research. It is a major hub in chromosomal research with a friendly and supportive atmosphere and a strong tradition of in-house collaborations.
Mitter, M., Gasser, C., Takacs, Z., Langer, CCH., Tang, W., Jessberger, G., Beales, CT., Neuner, E., Ameres, SL., Peters, JM., Goloborodko, A., Micura, R., Gerlich, DW. (2020). Conformation of sister chromatids in the replicated human genome. Nature. 586(7827):139-144