Cancer progression and resistance to therapies are direct consequences of alterations in the three-dimensional (3D) organization of the genome. It is increasingly clear that although genes and their regulatory elements, termed enhancers, are located far apart in the DNA, they interact by a looping mechanism to promote gene expression by RNA Pol II. This looping interaction is cell type specific, and is mediated by proteins like CTCF. Cancer cells typically hijack these looping interactions to mis-pair gene enhancer looping, resulting in activation of oncogene expression by RNA Pol II. However, CTCF mediated gene-enhancer looping, resulting in activation of gene expression by RNA Pol II in a...

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Cancer progression and resistance to therapies are direct consequences of alterations in the three-dimensional (3D) organization of the genome. It is increasingly clear that although genes and their regulatory elements, termed enhancers, are located far apart in the DNA, they interact by a looping mechanism to promote gene expression by RNA Pol II. This looping interaction is cell type specific, and is mediated by proteins like CTCF. Cancer cells typically hijack these looping interactions to mis-pair gene enhancer looping, resulting in activation of oncogene expression by RNA Pol II. However, CTCF mediated gene-enhancer looping, resulting in activation of gene expression by RNA Pol II in a genome-wide scale has not been accomplished in normal prostate cells or prostate cancer cells. The absence of this knowledge has limited our understanding of mechanisms by which gene expression gets altered during prostate cancer development. Our group has made tremendous progress in defining the landscape of RNA Pol II associated enhancer promoter looping in multiple prostate cancer models as well as normal prostate cells. We hypothesize the CTCF is a part of a molecular clamp that sandwiches RNA Pol II between enhancers and promoters. We propose that mis-regulation of multiple genes involved in prostate cancer development are due to alterations in the 3D architecture defined by CTCF. Based on our success with generating 3D maps of RNA Pol II transcription machinery using a technically challenging tool, ChIA-PET, we propose to extend this technique to understand the chromatin domains in prostate cancer by constructing 3D maps of CTCF. We propose to develop animal models that are castration resistant as well as enzalutamide resistant to validate the functional significance of these interactions. Successful accomplishment of the proposed research plan will help in the development of epigenetic therapies for cancer and will set the stage for personalized epigenomics.

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