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Epigenetic Basis For The Oncogenic Potential Of Idh Mutations, Chao Lu
Publicly Accessible Penn Dissertations
Although many complex diseases including cancer manifest aberrant cellular metabolism and chromatin structure, the molecular connection between two processes remains poorly understood. The metabolite, α-ketoglurate (αKG), is a critical co-factor for a number of chromatin modifying enzymes. Its structural analogue, 2-hydroxyglutarate (2HG), was recently identified as the product of cancer-associated mutations in isocitrate dehydrogenases (IDH). To determine whether metabolic perturbation can disrupt chromatin remodeling and transcription, I investigated the epigenetic consequences of 2HG-producing IDH mutations. In this thesis, 2HG was demonstrated to be a competitive inhibitor for αKG-dependent chromatin modifiers including TET family DNA hydroxylases and jumonji-C histone demethylases. Expression ...