Xingguo Zhu, PhD
Assistant Professor, Georgia Cancer Center, Department of Medicine, Medical College
Assistant Professor, Department of Pediatrics, Division of Hematology/Oncology
The Zhu laboratory is interesting in the function of transcription factor, NRF2, a master regulator for the oxidative stress response, in the physiological and pathophysiological conditions including sickle cell disease (SCD) and other types of malignant diseases. The research focus of the lab is to understand how NRF2 mediates gene expression and how this regulatory mechanism could be exploited to achieve therapeutic goals.
The Xingguo Zhu Lab
Health Sciences Campus
Georgia Cancer Center - M. Bert Storey Research Building
1410 Laney Walker Blvd., CN-4114, Augusta, GA 30912
Using human erythroid primary cells and NRF2 knockout SCD mouse model, the research in the lab will determine the important role of NRF2 in developmentally regulated hemoglobin switching during SCD development. Major research focus includes: 1) the role of NRF2 in the regulation of globin gene expression and switching. 2) Studies of the deleterious effect for downregulated NRF2 in SCD patients erythroid progenitor cells. 3) Using the NRF2 knockout SCD mouse model to determine the essential function of NRF2 on SCD pathophysiology. 4) explore small chemical compounds with NRF2 induction activity in SCD treatment. To achieve these objectives, the laboratory has successfully applied multiple molecular biotechnologies to extensively reveal the detailed molecular mechanism for NRF2 in human globin gene regulation, γ- to β-globin gene switching and their relevant for treatment of SCD.
A specific focus of NRF2 function in liver tumor is currently under exploration to reveal the NRF2 mediated multiomics mechanism in promoting liver tumor progression. Cancer cells experience aberrant epigenetic modification, especially for histone acetylation in solid tumors. One regulatory mechanism for histone acetylation is the availability of acetyl CoA as the source of the acetyl group to incorporate into lysine residues. Research in the lab demonstrates that NRF2 drives metabolic reprogramming in regulating acetyl CoA availability. Mechanistically, under nutrient-poor, more specifically, low glucose conditions, Nrf2 ablation impairs multiple metabolic pathways including glucose uptake, glycolysis and fatty acid metabolism, to reduce the availability of acetyl CoA. This reduction limits both metabolic energy generation for tumor cell growth and histone acetylation for gene regulation. A tight correlation of NRF2 expression with histone acetylation has been identified in human liver tumors. The findings in the lab implicate NRF2, in addition to its typical regulatory role on reactive oxygen species response, integrates metabolic and epigenetic programs to drive liver tumor progression.
Xingguo Zhu, Jianhua Ling, Ling Zhang, Wenhu Pi, Min Wu and Dorothy Tuan. A facilitated tracking and transcription mechanism of long-range enhancer function. Nucl Acids. Res. 2007;35, 5532-5544.
Xingguo Zhu, Yongchao Wang, Wenhu Pi, Hui Liu, Amittha Wickrema, Dorothy Tuan. NF-Y recruits both transcription activator and repressor to modulate tissue- and developmental stage-specific expression of human gamma-globin gene. Plos One. 2012;7, e47175
Tianxiang Hu, Wenhu Pi, Xingguo Zhu, Miao Yu, Hongseok Ha, Huidong shi, Jeong-Hyeon Choi, Dorothy Tuan. Long non-coding RNAs transcribed by ERV-9 LTR retrotransposon act in cis to modulate long-range LTR enhancer function. Nucleic Acids Res. 2017;45(8):4479-4492.
Xingguo Zhu, Biaoru Li, Betty S. Pace. NRF2 mediates γ-globin gene regulation and fetal hemoglobin induction in human erythroid progenitors. Haematologica. 2017;102(8):e285-e288.
Xingguo Zhu, Tianxiang Hu, Meng Hsuan Ho, Yongchao Wang, Miao Yu, Niren Patel, Wenhu Pi, Jeong_Hyeon Choi, Hongyan Xu, Vadivel Ganapsthy, Ferdane Kutlar, Abdullah Kutlar, and Dorothy Tuan. Hydroxyurea differentially modulates activator and repressors of γ-globin gene in erythroblasts of responsive and non-responsive patients with sickle cell disease in correlation with Index of Hydroxyurea Responsiveness. Haematologica. 2017;102(12):1995-2004.
Xingguo Zhu, Caixia Xi, Bobby Thomas, Betty S. Pace. Loss of NRF2 function exacerbates the pathophysiology of sickle cell disease in a transgenic mouse model. Blood. 2018;131(5):558-562.
Xingguo Zhu, Aluya R. Oseghale, Lopez H. Nicole, Biaoru Li, Betty S. Pace. Mechanisms of NRF2 activation to mediate fetal hemoglobin induction and protection against oxidative stress in sickle cell disease. Exp Biol Med. 2019; 244: 171–182.
Xingguo Zhu, Caixia Xi, Alexander Ward, Mayuko Takezaki, Huidong Shi, Kenneth R Peterson, Betty S Pace. NRF2 mediates γ-globin gene regulation through epigenetic modifications in a β-YAC transgenic mouse model. Exp Biol Med. 2020;245(15):1308-1318.