Zhiguo Zhang, PhD

Profile Headshot

Overview

Academic Appointments

  • Professor of of Epigenomics and Molecular Biology

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. 

Languages

  • Chinese

Credentials & Experience

Education & Training

  • PhD, Biochemistry, University of Utah College of Medicine

Research

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?

Research Interests

  • Epigenetic inheritance and Cancer Epigenetics

Grants

ACTIVE

1. R35GM118015-01   (Zhang, Z.)                           08/01/2016-07/31/2021                       6.24 calendar-months

NIH/NIGMS                                                            

Title: Mechanisms of Epigenetic Inheritance.

The goal of this R35 application to determine molecular mechanisms of epigenetic inheritance and to combine NIGMS R01 grants into one grant.

2. R01CA 204297-1   (Zhang, Z.)                            04/01/2017-03/31/2022

                                                                                 1.8 calendar-months

NIH

The epigenetic mechanisms of high-grade pediatric glioblastoma

The goal of this grant is to determine how H3.3K27M mutation found in high-grade pediatric brain tumors reprograms H3K27 methylation landscape and gene expression and identify potential therapeutic targets for this deadly tumor. This is a collaborative grant with Dr. David Daniels, a pediatric neurosurgeon, Dr. Jann Sarkaria, a clinician scientist with expertise in mouse models of brain tumors.

Selected Publications

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