Our laboratory’s research activities concern the interplay of diverse mechanisms that maintain and provide access to genetic information. These processes take place within the context of an organism’s genome, the complete DNA instruction set for biological processes that is present in every living cell. In organisms from yeast to humans, genomic DNA is highly compacted and organized by proteins to form a structure known as chromatin. Extraordinary levels of compaction are needed because the genomes of higher organisms, such as humans, contain on the order of two meters of DNA within a nucleus that is only a few micrometers in diameter. This implies that the entire human genome is compacted by more than 10,000-fold!
This very dense state of DNA creates both opportunities and challenges for the cell. On one hand, the three-dimensional folding of individual chromosomes creates territories, compartments, and domains that promote interactions between DNA segments that are located far apart along the DNA sequence. Such “action at a distance” is a common mechanism for biological regulation where one or more DNA-binding proteins simultaneously bind to two or more DNA sequences. On the other hand, it is easy to imagine that such a highly compacted state can promote entangling of DNA molecules leading to complex structures, and even knots. Knots that are formed in DNA can make genetic information inaccessible and even lead to cell death. The phenomenon is not unlike the universal experience of reaching into a bag or pocket to listen to some music or take a call, only to find that your earbud cables have conspired against you by becoming knotted!
A central focus of our work is understanding how a balance is achieved between maintenance of the genome’s compacted state and DNA accessibility. What mechanisms guide the three-dimensional folding of complex genomes inside the nucleus of a functioning cell? How is folding controlled thermodynamically and kinetically? And how does genome organization, in turn, regulate other cellular processes?
To answer these questions, we develop new molecular technologies and powerful computational and biophysical tools applied to both model and “real” systems. In addition, our lab employs innovative interdisciplinary approaches to investigate the physical and functional genomics of health and disease in human cells and those of other organisms. These methods rely on a novel fusion of biophysics/bioengi- neering with cutting-edge genetic/genomic tools.