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Center For Cancer Research National Cancer Institute
Cell Biology of Genomes Group

Having reached the milestone of sequencing entire genomes, fundamental issues in understanding human biology are how genomes are organized in living cells and how gene expression programs are regulated. My laboratory seeks to uncover how nuclear architecture and genome topology affect genome function in living cells. The importance of nuclear architecture in controlled genome expression is evident from the critical role nuclear reorganization plays in stem cell differentiation, carcinogenesis and cloning by nuclear transfer. To gain insight into nuclear function in vivo, we are applying a multifaceted approach to study the biophysical properties of proteins in living cells, the spatial organization of genome within the cell nucleus and the application of imaging methods to study pre-mRNA processing events.

To understand the nuclear environment in which genomes are expressed, we are probing the biophysical properties of proteins and chromatin using in vivo imaging. We are developing and applying a combination of photobleaching microscopy and computational methods to analyze the binding of chromatin proteins and transcription factors to cellular chromatin in situ. Our efforts are providing information about the global behavior of nuclear proteins and allow us to ascertain the kinetics and biogenesis of transcription complexes, intranuclear compartments and chromatin domains in single living cells. These approaches give unprecedented insights into dynamic aspects of genome expression and are revealing fundamental principles of cellular organization.

Following the completion of numerous whole genome sequences, a critical question in the field of genome biology is how genomes are organized within the cell nucleus and how genome topology affects gene expression. A major project in the laboratory is the mapping of genomes in space and time, using high-resolution microscopy methods, high-throughput imaging and computer simulations. We are studying the positioning of entire chromosomes and particular gene loci within the nucleus and we are testing how these arrangements change during differentiation and tumorigenesis.

Finally, we are investigating one of the most important mechanisms for regulating gene expression and generating protein diversity in higher organisms: alternative splicing. Defects in alternative splicing contribute to cancer and human diseases. However, it is still largely unclear how distinct splicing patterns are established under given physiological conditions. We have implemented combined molecular and imaging methods to elucidate cellular mechanisms that control alternative splicing.

Our cell biological studies of genomes and the cell nucleus are aimed at uncovering fundamental concepts of genome organization and nuclear function in vivo and this research is providing opportunities for applying these principles to human disease diagnosis, therapeutics and bioengineering.