Research Projects

The focus of our laboratory is the molecular biology of chromatin structures and their role in chromosome biology and genome function in health and disease.

In the nucleus of living cells, DNA rarely exists in its naked form; instead, it is packaged together with proteins into chromatin. Rather than acting as an inert scaffold for DNA, dynamic and flexible chromatin structures and modifications have profound effects on almost all aspects of chromosome behavior and genome function. Enzymes involved in many aspects of DNA metabolism such as transcription, DNA replication, recombination, and repair, as well as chromosome segregation, function in the context of this complex template. Furthermore, several such chromatin structures can be inherited during cell division thus providing epigenetic information overlaying the DNA sequence.

A large number of proteins involved in cancer development and human genetic disease function through modification of chromatin structures and interfere with normal chromatin function. For this reason, chromatin is emerging as a prime target for therapeutic intervention of disease. Our studies in yeast will contribute to a detailed understanding of the principal mechanisms underlying diseases in the context of chromatin and will provide the basis for future investigations of cognate components and processes in mammalian species.

The nucleosome is the basic building block of chromatin, consisting of DNA wrapped around an octamer of histone proteins. Differences in chromatin structures between adjacent regions specify the properties of those macrodomains, which we refer to as neighborhoods. Three principal mechanisms exist to regulate chromatin function and to create distinct chromosomal neighborhoods. First, histones are subject to a large variety of posttranslational modifications, including acetylation, phosphorylation, methylation, ubiquination and sumoylation. Consistent with this complexity, many different enzymes are involved in the addition and removal of these modifications. One of these, the essential histone acetyltransferase NuA4, is being studied in our laboratory. Second, members of the ATP-dependent class of chromatin remodeling enzymes alter histone-DNA contacts by several recognized means. The catalytic subunit of SWR1-Com, a protein complex that we discovered and study, belongs to this group of enzymes. Third, minor variants of the canonical histones with specialized functions are found in distinct chromosomal neighborhoods. These include the H2A variant H2A.Z, which is deposited by SWR1-Com to form a boundary for ectopic spread of heterochromatic structures. Over the last few years, our work, and that of others, has revealed functional and physical linkages between these three mechanisms and the processes they regulate.

Research in our laboratory touches on some of the fundamental questions in chromatin biology. These queries include how distinct chromosomal neighborhoods are established, how they function and interact with enzymes involved in DNA metabolism, what the functional differences between histone variants and canonical histones are, and how chromatin-remodeling complexes are regulated. We also examine the structure and function of a protein domain that is found in a shared subunit of SWR1-Com and NuA4 as well as in several proteins involved in leukemia and glioma. To gain insight into these fascinating questions, we apply innovative genomic and proteomic technologies and collaborate with research groups in the CMMT and across the world to complement our expertise.