Principal investigatorName: Wei QiAssociate Professor , PhD, Associate Professor
Position: Affiliation: School of Life Science and Technology
Honor: Education Background:
Working Experience:
Group Introduction Research Area:
Epigenetics and Translational Research
Research Interests:
Histone modification is a major epigenetic factor modifying gene transcription on top of inherited genetic information. It regulates cellular status such as proliferation and differentiation and designates the identity of specific cells. The machinery for histone modification is composed of writers (enzymes adding the modification to histones), erasers (enzymes removing the modification) and readers (proteins recognizing the modification and transduce signals). Mutation or dysfunction of these epigenetic machineries has been implicated in multiple diseases such as cancer, autoimmune diseases and metabolic diseases. My lab is focusing on dissecting the epigenetic characteristics of the disease and validating their pathophysiological functions using integrated approaches of epigenetics, chemical biology and gene editing. The goal of our work is to identify effective targets and potential lead compounds for therapeutic development, so that the patients will benefit. Research Achievement（1）PRC2（Polycomb Repressive Complex 2）is composed of core components EZH1/2, Suz12 and EED. It is the sole enzyme resposible for histone H3K27 methylation, which often associates with gene repression. Genetic alterations of EZH2/Suz12/EED has been found in multiple cancers and validated as driving events. PRC2 inhibitors targeting to the enzymatic subunit EZH1/2 or the allosteric subunit EED have been discovered and brought into anti-cancer clinical studies. (2）Adipose tissue plays important roles in animals.White adipose tissue (WAT) stores energy in lipids, while brown fat (BAT) is responsible for nonshivering thermogenesis through UCP1-1 mediated energy dissipation. Although epigenetic mechanisms modulate differentiation in multiple lineages, the epigenetic regulation of brown adipocyte differentiation is poorly understood. By screening a collection of epigenetic compounds, we found that Lysine-Specific Demethylase 1 (LSD1) inhibitors repress brown adipocyte differentiation. RNAi-mediated Lsd1 knockdown causes a similar effect, which can be rescued by expression of wild-type but not catalytic-inactive LSD1. Mechanistically, LSD1 promotes brown adipogenesis by demethylating H3K4 on promoter regions of Wnt signaling components and repressing the Wnt pathway. Furthermore, deletion of Lsd1 in mice leads to inhibition of brown adipogenesis, validating the pivotal role of LSD1 in brown fat development in vivo. In addition, we identified Gpnmb as a liver-secreted factor regulating lipogenesis in WAT. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes. Representative Publications (*First Author, # Corresponding Author)
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