My laboratory investigates the functions of chromatin – specifically histones and their post-translational modifications – in regulation of cellular metabolism and physiology. We also study how these functions may be altered in and contribute to human disease such as cancer. We use molecular biology, genetics and biochemistry to address questions, and employ model systems that are most appropriate for the question being asked. Our major findings include identification of a unique histone acetylation site as a critical target for oncogenic transformation by viral oncogenes, the first predictive association of epigenetic alterations with clinical outcome of cancer patients, the discovery of an unusual function of histone acetylation in regulation of intracellular pH and uncovering how histones have evolved to enable greater compaction of genomes that are disproportionately too large for the nuclear volume. We are currently investigating an unprecedented role for histones in copper homeostasis. Although histones participate in eukaryotic genome compaction and epigenetic gene regulation, it is unclear whether these functions served as the driving force for the evolution of ancestral histones or were necessary for the formation of the first eukaryotic common ancestor. These considerations raised the possibility that histones may have an additional, unknown function. We have recently discovered that the histones H3-H4 tetramer is an enzyme with copper reductase activity, providing biousable copper for cellular and mitochondrial chemistry. This enzymatic function has fundamental implications for understanding the origin and biology of eukaryotes, and may inform on a wide range of human diseases such as cancer and neurodegeneration in which alteration of copper homeostasis is implicated.
Siavash K. Kurdistani, MD