Oncogenic triggers and their influence on 3D chromosomal architecture

New York University School Of Medicine, New York NY

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Abstract

PROJECT 3: PROJECT SUMMARY Recent studies connected 3D nuclear and chromosomal architecture to the regulation of gene expression in multiple tissues and cell types. PIs in this Program Project were some of the first to link 3D topology to cellular transformation in human leukemia. We identified mutations that can impact DNA looping (targeting CTCF and the Cohesin complex) and mapped nuclear topology in T cell leukemia (T-ALL). Also, in collaboration with the Computational Core, we developed and refined computational tools that enable us to study such 3D interactions in cancer genomes, starting with the characterization of large 3D structures, including chromosomal compartments and topological associated domains (TADs). What we propose here is to move from higher-order chromatin interactions to looping events that involve specific interactions between distinct DNA elements. More specifically, we will focus on 3D ‘cis regulatory element (CRE) hubs’, DNA elements that interact with multiple other DNA loci, including promoters and enhancers. We continue to focus on T-ALL but we now expand our studies to related pediatric blood neoplasms, including early T cell progenitor (ETP), B cell-ALL (B-ALL), and, in collaboration with Project 2, B cell lymphoma, all heterogenous blood cancers with distinct cells of origin and phenotypic overlaps. We focus on transcriptional regulation of these neoplasms and test the hypothesis that CRE hubs coordinate cell type specific gene networks serving as 'headquarters' of cell identity that contribute to the control of transformation, tumor progression and response to drug treatment. We test this hypothesis in three Aims. Initially, we map CRE hubs and study their biological significance as well as their relationship to genetic background. Also, we study their intra- and inter-patient molecular heterogeneity of 3D hubs in leukemia, using a battery of single cell tools and primary human samples. Finally, we propose a mechanistic understanding of 3D CRE hub function by targeting using in silico and CRISPR/Cas9-mediated approaches.