Abstract 1024: Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation

Abstract

Abstract INTRODUCTION: The organization of chromatin within the nucleus into hierarchical three-dimensional (3D) structures plays a key role in the regulation of gene expression. Differences in 3D architecture, such as the presence or absence of “loops” between specific enhancers and their target genes, are a major driver of transcriptional and phenotypic variation. By determining the accessibility of genes to transcriptional machinery and distal regulatory regions, mechanisms mediating oncogene activation can be discerned. Recent studies have implicated pathogenic alterations in genome topology with the activation of proto-oncogenes in a multitude of cancers. METHODS: To characterize the topological changes associated with different cancer states, we developed a computational suite of tools that facilitates the systematic discovery, annotation, and visualization of features in chromatin topology and assigns statistical confidence estimates to regions with variability between cellular phenotypes. Our framework facilitates the integration of heterogeneous genomic data, including gene expression, histone modification, DNA methylation, open chromatin, and genetic variation, to further characterize changes in 3D genome. Ultimately, we propose a joint model that functionalizes the effect of epigenetic modifications on transcription as mediated through hierarchical chromatin structure. RESULTS: We identify regions of topological variation unique to breast cancer, cervical cancer, glioblastomas with and without an IDH1 mutation, melanoma, and leukemia. Patterns of disrupted insulation and subsequent localization of enhancers to proto-oncogenes can be attributed to variation in the epigenome, including variation in DNA methylation and open chromatin, at distal regulatory regions. These 3D alterations provide a mechanism for activation of specific oncogenic pathways, including signaling mediated by p38, PLK3, and BRCA. CONCLUSIONS: Variable patterns of chromatin topology provide a unique signature and mechanism of oncogenes for the cancer phenotypes considered. Additionally, our framework provides a novel means for interpreting epigenetic variability, particularly at distal regulatory regions, and explaining transcriptional variation associated with cancer phenotypes as mediated through structural changes in the DNA. Citation Format: Caleb Lareau, Martin Aryee. Genome-wide examination of topological variability reveals cell type-specific mechanisms of oncogene activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1024. doi:10.1158/1538-7445.AM2017-1024