Abstract IA12: Long-range gene regulation in the context of chromatin domains

Abstract

Abstract The 3D organization of the genome is critical for gene regulation, genome stability and faithful transmission of chromosomes to daughter cells. We apply Chromosome Conformation Capture-based technologies to determine how cells fold their chromosomes and to discover the mechanisms that drive the spatial organization of genomes. I will discuss our recent proposal that in interphase nuclei mammalian chromosomes are hierarchically organized (Gibcus and Dekker, 2013). First, at the nuclear level, chromosomes are compartmentalized into large multi-Mb domains that are either active and open or inactive and closed. These compartments themselves are composed of smaller sub-Mb Topologically Associating domains (TADs) (Dixon et al. 2012, Nora et al. 2012). Finally, long-range gene regulation occurs within TADs through long-range looping interactions between genes and regulatory elements. TAD organization and their role in gene regulation have important implications in cancer cells. I will highlight how genomic rearrangements in cancer genomes can lead to altered TAD organization and inappropriate gene expression, including increased expression of cancer promoting genes, and repression of cancer suppressing genes. I will also highlight two new studies from my laboratory that reveal different roles of TADs in chromosome-wide gene regulation along the dosage compensated X-chromosomes. First, in C. elegans we find that a Condensin complex mediates TAD formation and dosage compensation. Second, in mouse the dosage compensated X chromosome folds in a unique way with global loss of TADs. Citation Format: Job Dekker. Long-range gene regulation in the context of chromatin domains. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr IA12.