Zhiguo Zhang, PhD
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 is nucleosome assembly of histone H3 variant H3.3 regulated?
6) How do different histone mutations promote tumorigenesis of brain and bone tumors?
1. 6. 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. 19. 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. 30. 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. 54. 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