Zhiguo Zhang, PhD
There are two long-term goals in my laboratory. First, we are interested in determining how epigenetically determined chromatin states are inherited during S phase of the cell cycle and how alterations in this process impact genome instability. We are using yeast, mouse embryonic stem cells as well as human cells to address this fundamental question in the chromatin and epigenetic field. Currently, we are focusing on determining how nucleosomes, the basic repeat unit of chromatin, are assembled following DNA replication. Second, we are interested in determining how epigenetic alterations contribute to tumorigenesis and drug resistance. Towards this goal, we are focusing on determining how mutations on histones promote tumorigenesis using brain and bone tumors as models and how epigenetic changes drive drug resistance in brain tumors.
There are two major research interests and goals in my laboratory: epigenetic inheritance and cancer epigenetics. We are using different systems including yeast, mouse ES cells, human tumor cell lines as well as primary tumor samples and a combination of genetic, biochemical and system biology approaches to achieve these two long-term goals.
How epigenetic states are transmitted into daughter cells so called epigenetic inheritance is one of the most challenging, but yet poorly understood, questions in the chromatin and epigenetic fields. Factors involved in epigenetic inheritance also play an important role in maintenance of genome integrity. In recent years, it has been clear that epigenetic alterations contribute to the development of a variety of diseases including cancer. However, how alterations in epigenetic landscape contribute to tumorigenesis is largely unexplored. Therefore, we are asking the following major questions to study molecular mechanisms of epigenetic inheritance and cancer epigenetics. We hope that these studies will not only increase our fundamental knowledge about the critical cellular processes, and but will help combat cancer caused by epigenetic alterations. The following are major questions we are addressing in my laboratory. 1) How are parental histone H3-H4 tetramers, which carry modifications for inheritance, assembled into nucleosomes? 2) How alterations in DNA replication-coupled nucleosome assembly contribute to genome instability and cell lineage maintenance of mouse embryonic stem cells? 3) How do chromatin regulators impact DNA synthesis of leading and lagging strands? 4) How is the stability of replication forks maintained under replication stress? 5) How do different histone mutations promote tumorigenesis of brain and bone tumors?
1) Determine how parental histone H3-H4 tetramers, which carry modifications for inheritance, are assembled into nucleosomes in yeast and mammalian cells
2) Elucidate how chromatin regulators impact DNA synthesis of leading and lagging strands and how the stability of replication forks maintained under replication stress
3) Understand histone mutations reprogram cancer epigenome and promote tumorigenesis of brain and bone tumors
4) Determine how epigenetic changes promote drug resistance in brain tumors
1. Fang D, Gan H, Lee J, Han J, Wang Z, Riester SM, Jin L, Chen J, Zhou H, Wang J, Zhang H, Yang N, Bradley EW, Ho TH, Rubin BP, Bridge JA, Thibodeau SN, Ordog T, Chen Y, van Wijnen AJ, Oliveira AM, Xu R, Westendorf JJ, Zhang Z. : (2016) The histone H3.3K36M mutation reprograms the epigenome of chondroblastomas. Science 352: 1344-1348
2. Yu C, Gan H, Han J, Zhou ZX, Jia S, Chabes A, Farrugia G, Ordog T, Zhang Z: (2014) Strand-specific analysis shows protein binding at replication forks and PCNA unloading from lagging strands when forks stall. Molecular Cell 56: 551-563
3. Han J, Zhang H, Zhang H, Wang Z, Zhou H, Zhang Z: (2013) A Cul4 E3 ubiquitin ligase regulates histone hand-off during nucleosome assembly. Cell 155: 817-829
4. Su D, Hu Q, Li Q, Thompson JR, Cui G, Fazly A, Davies BA, Botuyan MV, Zhang Z, Mer G. : (2012) Structural basis for recognition of H3K56-acetylated histone H3-H4 by the chaperone Rtt106. Nature 483: 104-107
5. Li Q, Zhou H, Wurtele H, Davies B, Horazdovsky B, Verreault A, Zhang Z. : (Cell) Acetylation of histone H3 lysine 56 regulates replication-coupled nucleosome assembly. 134: 244-255
6. Han J, Zhou H, Horazdovsky B, Zhang K, Xu RM, Zhang Z: (2007) Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication. Science 315: 653-655