Chromatin encodes epigenetic information and maintains genome stability. Defects in mechanisms regulating the inheritance of epigenetic information and chromatin structure may contribute to disease pathogenesis. The laboratory of Zhiguo Zhang, Ph.D., focuses on determining how epigenetically determined chromatin states are inherited during S phase of the cell cycle and translating basic science discoveries into novel therapeutics and diagnostic tools.
Dr. Zhang's research has been published in Science, Nature, Cell, Proceedings of the National Academy of Sciences, Genes and Development, and Molecular Cell and has been funded by the National Institutes of Health, the Leukemia and Lymphoma Society, and the state of Minnesota.
- Identification of factors and mechanisms regulating nucleosome assembly and cellular senescence. Chromatin structure governs a number of cellular processes, including DNA replication, gene transcription and DNA repair. The basic repeating unit of chromatin is the nucleosome, which consists of 146 base pairs of DNA wrapped around a histone octamer. Using a combination of genetic and biochemical approaches, Dr. Zhang's group is addressing how newly synthesized histones H3-H4 are deposited onto DNA and how parental H3-H4 are transferred to replicating DNA for nucleosome formation during S phase of the cell cycle. In addition, his group is determining how nucleosome assembly factors regulate cellular senescence. Dr. Zhang's group has made many important contributions to the nucleosome assembly field through the discovery of factors and mechanisms regulating nucleosome assembly in yeast and mammalian cells, including discoveries of the histone chaperone Rtt106, histone acetyltransferase Rtt109 and how post-translational modifications on histone proteins regulate nucleosome assembly pathways.
- Determine how the inactivated X-chromosome in female mice is maintained during S phase of the cell cycle. Female mammals have two X-chromosomes. To balance X-chromosome gene expression, one X-chromosome in female mammals is inactivated during early embryogenesis. Once inactivated, the inactivated X-chromosome (Xi) remains silenced during subsequent cell divisions. Dr. Zhang's group is interested in determining how Xi silencing is maintained. His group has performed a genome-wide shRNA screen to identify genes involved in the maintenance of Xi silencing in female mouse cells and is addressing how select candidate genes function in the maintenance of Xi silencing.
- Determine how epigenetic changes in gene expression contribute to the development of cancer drug resistance. Acquired resistance to chemotherapeutic drugs is a major obstacle in the treatment of many forms of cancer. Acquired drug resistance can arise by a number of mechanisms, including altered drug efflux, gene expression changes and acquired genetic mutations. Dr. Zhang's group is testing the hypothesis that epigenetic changes in gene expression contribute to the development of drug resistance, using brain tumors and ovarian cancer as models.
- Identification of small molecular inhibitors against Rtt109 for treatment of fungal infection. Fungal infection has risen significantly since late last century mainly due to the increased numbers of immunocompromised patients. Despite significant advances made in fighting fungal infection, the mortality rate from opportunistic fungal infections remains high. One of the primary reasons for the lack of effective antifungal therapy is the difficulty in identifying fungi-specific molecular targets for intervention. Dr. Zhang's group was one of the first to discover a unique histone acetyltransferase, Rtt109, that acetylates histone H3 lysine 56 in Saccharomyces cerevisiae. Remarkably, while sequence homologs of Rtt109 are present in other fungal species, no sequence homolog of Rtt109 has been identified in humans or other mammals. Thus, Rtt109 is an attractive target for the discovery of novel compounds that prevent fungal infection. In collaboration with others at Mayo Clinic and the University of Minnesota, Dr. Zhang's team is identifying small molecular inhibitors against Rtt109 and testing the efficacy of these inhibitors against fungal infection using animal models.
Significance to patient care
Improvement of patient care relies, at least in part, on understanding molecular events taking place inside the cell. Epigenetics is the new frontier of biomedical research and medicine. Epigenetic alterations have been documented in a variety of diseases, including cancer and aging. Thus, factors involved in epigenetic inheritance may serve as novel therapeutic targets or prognosis markers. Research by Dr. Zhang and his team aimed at determining the molecular mechanisms contributing to epigenetic inheritance will likely significantly impact patient care in the future.
- Scholar, Leukemia and Lymphoma Society, 2009-2014
- Director, Epigenetic Development Laboratory, Center for Individualized Medicine, Mayo Clinic, 2012-present