The Development of Chemical and Computational Tools to Study Transcriptional Regulation in Cancer
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CitationFederation, Alexander Joel. 2015. The Development of Chemical and Computational Tools to Study Transcriptional Regulation in Cancer. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractEukaryotic gene regulation is a complex process requiring the action of many multicomponent complexes in the cell. Specific inhibitors of chromatin-associated factors allow the functional study of protein domains without genetic removal of the entire protein. Here, two small molecule probes were used to study the role of DOT1L and BET proteins in cancer biology.
DOT1L is a histone methyltransferase with activity correlating with positive regulation of transcription. In MLL-rearranged leukemia, DOT1L is recruited aberrantly to early developmental transcription factors, leading to their inappropriate expression and leukemia maintenance. The development of an assay platform for DOT1L allowed the investigation of many small molecule DOT1L inhibitors, leading to compounds with improved potency and pharmacokinetics.
Studying the action of BET bromodomain inhibitors led to the identification of super enhancers, large tissue-specific regulatory elements driving the expression of genes critical for the function of the cell. Super enhancers are often found in oncogenic translocation events, especially in B cell malignancies. This study identified a subset of super enhancers that promote off-target DNA damage from the B cell antibody diversity enzyme AID, leading to double strand break events and translocations.
Super enhancers also regulate the expression of master transcription factors (TFs) in a given cell type. Using the topology of the super enhancer, the sites of master TF binding can be predicted, allowing the construction of network models for transcriptional regulation. These models were built in a large number of healthy and diseased cell types, including the pediatric malignancy medulloblastoma. In medulloblastoma, a network motif was identified that matches an expression pattern seen in a transient cell population in the developing cerebellum, providing evidence for the previously unknown cell of origin for Group 4 medulloblastoma.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:17463980
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