ID: 7056682 (Ref.No. dc46dec2)
Posted: February 28, 2019
Application Deadline: Open Until Filled
Investigating Chromatin Dysregulation due to Aberrant Dioxygenase Function in Human Pathology
A postdoctoral fellowship position is available in Dr. Abhishek Chakraborty’s newly established laboratory in the Department of Cancer Biology at the Cleveland Clinic. The laboratory is part of Cleveland Clinic’s GU Malignancies Research Center and has close ties to both basic researchers as well as GU clinicians at the Cleveland Clinic and the broader Case Comprehensive Cancer Center.
The laboratory is interested in the relevance of oxygen- (and 2-oxo-glutarate) dependent dioxygenases in cellular physiology, particularly in oxygen sensing and human disease. The laboratory is especially interested in studying the oxygen-dependent JmjC histone demethylases (e.g. KDMs) to 1) fundamentally understand the regulation and biological importance of hypoxia-dependent changes in chromatin; and 2) exploit dioxygenase dysfunction to identify therapeutically targetable vulnerabilities in human cancer, particularly kidney cancer.
Two notable publications highlight our contributions in these areas. First, we discovered that the H3K27 histone demethylase UTX/KDM6A is a novel cellular oxygen sensor that directly links physiological oxygen availability to transcriptional readout. KDM6A function, therefore, governs critical oxygen-dependent biological programs, including the regulation of cell state [Chakraborty AA et al. Science. In Press]. Second, by studying the compensatory mechanisms that allow kidney cancer cells to survive even in the face of profound chromatin dysregulation, we identified the H3K27 histone methyltransferase EZH1 as a targetable dependency in kidney cancer [Chakraborty AA et al. Science Transl Med. 2017 (398). pii: eaal5272]. This work is now being developed to begin exploring the feasibility of clinically targeting EZH1 in kidney cancer patients.
In addition to these discoveries, the laboratory has recently uncovered that the chromatin dysfunction in kidney cancer routinely affects enhancer-dense genomic regions called “Super-enhancers”. In other biological contexts, including other cancers, Super-enhancers have been shown to mark some of the most important genes involved in determining cellular state. These findings have motivated studies in the Chakraborty laboratory to identify Super-enhancer targets whose function is essential for kidney cancer cells, with the hope that, in time, (some of) these candidates could be nominated as potential therapeutic targets in kidney cancer.
The major techniques/areas of interest in the laboratory are Biochemistry [Protein purification and Enzymatic Assays], Molecular Biology [Cloning, Western Blotting, etc], Proteomics, Cancer Biology [in vitro and in vivo tumor models], Cellular Metabolism [steady state and flux-balance analysis], Pharmacology [drug discovery and delivery], Genomic analysis [RNA-Seq and ChIP-Seq data], and Whole-genome and Custom (mini-pool)Genetic Screens [both positive selection (gain-of-function) and negative selection (loss-of-function) screens].
The ideal candidate would have a M.D., Ph.D., or M.D./Ph.D. degree with interests and expertise in one or more of these areas. A collaborative and collegial work ethic, a strong commitment to basic cancer research, and outstanding verbal and communication skills are all required.
The position will provide a unique and multidisciplinary exposure to chromatin function, tumor metabolism, molecular oncology, drug development, and clinical collaborations.
Candidates with an interest in the position should email their CV and contact information for 3 references to:
Abhishek A. Chakraborty, Ph.D.
GU Malignancies Research Center
Lerner Research Institute
Cleveland Clinic, OH
Cleveland Clinic is pleased to be an equal employment/affirmative action employer: Women/Minorities/Veterans/Individuals with Disabilities. Smoke/drug free environment.