PHARM Medicinal Chemistry
College of Pharmacy
College of Pharmacy
Characterization and Repair Mechanism of DNA-Protein Cross-Links; Smoking Induced Epigenetics Changes: Role of DNA Demethylation
This research group is using MSI for three projects:
- Cisplatin is a common anticancer drug which has been shown to be able to induce DNA-Protein cross-links. As DPC is hypothesized to be toxic and mutagenic, it is important to know where are the hot spot for the DPC formation across genome. Thus, the researchers are modifying CHIP-seq into DPC-seq and mapping the DPC formation across genome after cisplatin treatment. This study will shed new light on the drugs metabolism and toxcity evaluation.
- Cytosine methylation (5-methylcytosine (MeC)) regulates gene expression in a tissue-specific manner. These methylation marks are introduced by DNA methyltransferases (DNMTs), which catalyze de novo methylation of CpG sites and maintain DNA methylation patterns to allow for activation and inactivation of specific genes. Cytosine methylation patterns are stable in normal somatic tissues, but are significantly altered in many diseases including cancer, asthma, and autism. Ten or eleven translocation proteins 1-3 (Tet) catalyze α-ketoglutarate dependent oxidation of MeC to 5-hydroxymethyl-cytosine (hmC), 5-formylcytosine (fC), and 5-carboxylcytosine (caC). These oxidized forms of MeC are not recognized by DNMTs and are removed via base excision mechanism, leading to gene reactivation. Furthermore, studies in the brain have shown that hmC, fC, and caC can be recognized by specific protein readers and may have their own function in human cells. Many key questions remain in regard to the biological roles of Tet proteins and the oxidized forms of MeC in normal cells and in human disease. The researchers employ quantitative proteomics to establish the biological functions of Tet proteins and oxidized forms of MeC in the lung. These studies will identify protein readers of MeC, hmC, fC, and caC in human bronchial epithelial cells using quantitative proteomics. This will contribute to basic understanding of epigenetic regulation in human cells and will help identify novel targets for therapeutic interventions. The researchers are also trying to design next generation inhibitors of Tet with specific inhibition to each Tet isoforms. This study could generate small molecule tools to study Tet function and could also be drug candidate to treat diseases caused bey overexpression of Tet.
- DNA methylation is proposed to be epigenetic signals and can regulate nearby gene expression by recruiting specific protein readers. Preliminary studies in this lab have found a global alteration of DNA methylation after triggering inflammation. In addition, inflammation is found to be a high risk factor of lung cancer development. Therefore, the researchers hypothesized that this epigenetic mechanism could serve as a bridge between inflammation and lung cancer. They will compare epigenomics (DNA methylation/hydroxymethylation), transcriptomics, and proteomics changes in A/J mice treated with cigarette smoke (CS), the inflammatory agent LPS, and the tobacco carcinogen NNK. Integration of these -omics datasets will provide a complete view of inflammation induced changes at molecular level and guide the researchers for therapy development in the future.
Dr. Juan Abrahante Llorns
Professor Natalia Tretyakova