Contribution of 3D genome topological domains to genetic risk of cancers: a genome-wide computational study

Abstract

Background Genome-wide association studies have identified statistical associations between various diseases, including cancers, and a large number of single-nucleotide polymorphisms (SNPs). However, they provide no direct explanation of the mechanisms underlying the association. Based on the recent discovery that changes in three-dimensional genome organization may have functional consequences on gene regulation favoring diseases, we investigated systematically the genome-wide distribution of disease-associated SNPs with respect to a specific feature of 3D genome organization: topologically associating domains (TADs) and their borders. Results For each of 449 diseases, we tested whether the associated SNPs are present in TAD borders more often than observed by chance, where chance (i.e., the null model in statistical terms) corresponds to the same number of pointwise loci drawn at random either in the entire genome, or in the entire set of disease-associated SNPs listed in the GWAS catalog. Our analysis shows that a fraction of diseases displays such a preferential localization of their risk loci. Moreover, cancers are relatively more frequent among these diseases, and this predominance is generally enhanced when considering only intergenic SNPs. The structure of SNP-based diseasome networks confirms that localization of risk loci in TAD borders differs between cancers and non-cancer diseases. Furthermore, different TAD border enrichments are observed in embryonic stem cells and differentiated cells, consistent with changes in topological domains along embryogenesis and delineating their contribution to disease risk. Conclusions Our results suggest that, for certain diseases, part of the genetic risk lies in a local genetic variation affecting the genome partitioning in topologically insulated domains. Investigating this possible contribution to genetic risk is particularly relevant in cancers. This study thus opens a way of interpreting genome-wide association studies, by distinguishing two types of disease-associated SNPs: one with an effect on an individual gene, the other acting in interplay with 3D genome organization.

CTCF: A misguided jack-of-all-trades in cancer cells

“…Similarly, mutations within TAD boundaries are also enriched in a variety of cancers, albeit usually with considerable cancer-type specificity for the affected boundaries [98] , [99] , [100] , [101] . A detailed study in T cell acute lymphoblastic leukemia (T-ALL) cells identified micro-deletions near oncogenes that removed CBSs from TAD boundaries [96] .…”

Epigenetics Role in Spermatozoa Function: Implications in Health and Evolution—An Overview

“…Some studies point out that regions with histones contain imprinted genes, ncRNAs, or homeobox genes, while others indicate that they are regions with low gene density (intergenic, repetitive, or retrotransposon) [ 16 , 18 , 22 , 27 ]. During development, the three-dimensional structure of chromatin and its distribution in the nucleus will change in each cell, defining each cell type [ 48 ]. The beginning of the development would require the reset of methylation marks by early active and late passive demethylation [ 16 ].…”

3D genome alterations in T cells associated with disease activity of systemic lupus erythematosus

“…Recently, disease-associated single-nucleotide polymorphisms (SNPs) as well as variations were shown to affect the 3D genomic structure 34 35. To further elucidate the roles of SLE-associated SNPs in 3D genomic structure, we compared the difference in loop strength at SNP loci between the patients with SLE and the HCs without focusing on the 391 SLE-associated loop set.…”