Spatial Genome Organization as a Framework for Somatic Alterations in Human Cancer

Abstract

Genomic material within the nucleus is folded into successive layers in order to package and organize the long string of linear DNA. This hierarchical level of folding is closely associated with transcriptional regulation and DNA replication. Microscopic studies concluded that genome organization inside the nucleus is not random and chromosomes within the nucleus create territories1. More recent chromosome conformation studies have revealed that mammalian chromosomes are structured into tissue-invariant topologically associating domains (TADs) where the DNA within a given domain interacts more frequently together than with regions in other domains2,3. Genes within the same TADs represent similar expression and histone-modification profiles4. In addition, enhancer-promoter pairs within the same TAD respond similarly to hormone induction5 or differentiation cues6. Therefore, regions separating different TADs (boundaries) have important roles in reinforcing the stability of these domain-wide features. Indeed, TAD boundary disruptions in human genetic disorders7,8 or human cancers lead to misregulation of certain genes9,10, due to de novo enhancer exposure to promoters. Here, to understand effects and distributions of somatic structural variations across TADs, we utilized single nucleotide variations, deletions, inversions, tandem-duplications and complex rearrangements from 2658 high-coverage whole genome sequencing data across various cancer types with paired normal samples. We comprehensively profiled structural variations with respect to their effect on TAD boundaries, on the regulation of genes in human cancers.