Characterization and Disruption of Cis Regulatory Elements in Cancer
CitationZeid, Rhamy. 2016. Characterization and Disruption of Cis Regulatory Elements in Cancer. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractEnhancers are cis regulatory elements that play key roles in the control of cell-type specific gene expression programs. In cancer, enhancer deregulation plays a key role in maintaining gene regulatory programs that underlie an oncogenic state. This dissertation focuses on understanding and modulating aberrant enhancer activity to identify potential vulnerabilities in human cancers. These studies were empowered by evolving technologies in genome-wide measurements of enhancer factors, computational approaches, and chemical and genetic tools to disrupt enhancer function.
In high-risk pediatric neuroblastoma, the transcription factor MYCN is frequently amplified and treatment options for these patients are largely ineffective thus establishing the need for improved therapeutic options. To identify previously unrecognized dependencies in neuroblastoma, we generated genome-wide maps of the active enhancer gene regulatory landscape leading to the identification of ID1 as an uncharacterized dependency in neuroblastoma. These results outline a strategy to identify alternative therapeutic avenues based on a holistic understanding of aberrant enhancer activity.
While MYCN amplification is the defining feature of high-risk neuroblastoma, a detailed mechanistic understanding of oncogenic transcriptional rewiring has been stalled by a lack of genome-wide binding data.
Here we present the dynamic and temporally resolved landscape of genome-wide MYCN occupancy in neuroblastoma. We find that deregulated MYCN binding at enhancers (termed enhancer invasion) is critical to maintaining the oncogenic station and identify the lineage specific transcription factor TWIST1 as a key collaborator and synthetic lethality of oncogenic MYCN. These data suggest that MYCN enhancer invasion shapes transcriptional amplification in neuroblastoma to promote tumorigenesis.
The development of small molecule inhibitors of the bromodomain and extra-terminal (BET) family of proteins provides a pharmacological strategy to inhibit enhancer activity. The efficacy of BET inhibition in several cancers has prompted efforts to predict and understand mechanisms of resistance to BET inhibition. Here, we use a newly developed class of small molecules to pharmacologically induce targeted degradation of the BET family. In triple negative breast cancer, we demonstrate that targeted BET family degradation effectively overcomes BET inhibitor resistance. These studies suggest BET degradation as a strategy to overcome BET inhibitor resistance and further disrupt and dissect enhancer activity in cancer.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:33493536
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