The long-term goal of my research program is to exploit aberrant 3D structure of cancer genomes as a new therapeutic avenue for cancer treatment. The first step towards this goal is to determine how chromatin regulators, some of the most frequently mutated genes in cancer, rearrange chromosome structure during carcinogenesis. My independent laboratory recently discovered a novel molecular mechanism of altered chromosome folding in cancer: formation of chromatin contact hubs by the BRD4-NUT fusion oncoprotein that drives NUT carcinoma. Pharmacological intervention causes both NUT carcinoma cell differentiation and disrupts these hubs, revealing the potential of altering chromatin structure as...

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The long-term goal of my research program is to exploit aberrant 3D structure of cancer genomes as a new therapeutic avenue for cancer treatment. The first step towards this goal is to determine how chromatin regulators, some of the most frequently mutated genes in cancer, rearrange chromosome structure during carcinogenesis. My independent laboratory recently discovered a novel molecular mechanism of altered chromosome folding in cancer: formation of chromatin contact hubs by the BRD4-NUT fusion oncoprotein that drives NUT carcinoma. Pharmacological intervention causes both NUT carcinoma cell differentiation and disrupts these hubs, revealing the potential of altering chromatin structure as a therapeutic strategy in cancer.

I will now utilize my experience and expertise in chromosome biology to investigate how altered chromatin structure relates to cancer cell viability in other widespread and aggressive malignancies. Specifically, the first objective is to determine how NSD3 and SETD2, an oncogene and tumor suppressor, respectively, alter the spatial organization of DNA that in turn alters transcription regulation during tumor progression in lung cancer. Next, we will tackle dominant-negative ‘oncohistone’ mutations in pediatric brain and bone cancer. The second objective will use innovative 3D genomics technologies to investigate how histone H3K27M and H3K36M mutations block differentiation by rewiring enhancer-promoter interactions thereby altering gene expression.

The immediate goal of this proposal is to reveal the molecular basis of abnormal chromatin folding in cancer. One consequence is fundamental, broadening our understanding that chromatin dysregulation in cancer not only occurs in 1D with respect to patterns of epigenetic modifications, but also reorganizes the 3D structure of the genome. A second long-term consequence is applied, realizing that chromatin structure itself is a therapeutic vulnerability thereby opening new avenues for cancer treatments.

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