Abstract
The human genome is organized into topologically associating domains (TADs), which represent contiguous regions with a higher frequency of intra-interactions as opposed to inter-interactions. TADs contribute to gene expression regulation by restricting the interactions between their regulatory elements, and TAD disruption has been associated with cancer. Here, we provide a proof of principle that mutations within TADs can be used to predict the survival of cancer patients. Specifically, we constructed a set of 1467 consensus TADs representing the three-dimensional organization of the human genome and used Cox regression analysis to identify a total of 35 prognostic TADs in different cancer types. Interestingly, only 46% of the 35 prognostic TADs comprised genes with known clinical relevance. Moreover, in the vast majority of such cases, the prognostic value of the TAD was not directly related to the presence/absence of mutations in the gene(s), emphasizing the importance of regulatory mutations. In addition, we found that 34% of the prognostic TADs show strong structural perturbations in the cancer genome, consistent with the widespread, global epigenetic dysregulation often observed in cancer patients. In summary, this study elucidates the mechanisms through which non-coding variants may influence cancer progression and opens new avenues for personalized medicine.
Highlights
The need for an efficient high-level organization of the genomic DNA, especially in a spatial sense, is obvious given the enormous amount of information stored in the eukaryotic genome.the human genome is three-dimensionally organized into topologically associated domains (TADs), which are hundreds of kilobases to megabases (Mb) in size and encompass multiple genes and regulatory elements [1]
To construct a single consensus topologically associating domains (TADs) map representing the most prevalent features of the three-dimensional organization of the human genome, we examined the number of original TAD
We first calculated a “conservation score” and a “boundary score” within 40-kilo base windows across the entire genome. While the former estimates the probability of the nucleotides in the window being comprised within a TAD, the latter estimates the probability that the window encompasses one or more TAD boundaries
Summary
The need for an efficient high-level organization of the genomic DNA, especially in a spatial sense, is obvious given the enormous amount of information stored in the eukaryotic genome.the human genome is three-dimensionally organized into topologically associated domains (TADs), which are hundreds of kilobases to megabases (Mb) in size and encompass multiple genes and regulatory elements [1]. Binding sites for the insulator protein CCCTC-binding factor (CTCF) and the protein complex cohesin were later found to be enriched in TAD boundary regions (TBRs) and to contribute to the confinement of chromatin loops within the TADs [3]. This organization into domains and loops is thought to serve as a foundation for the interaction of regulatory elements, which in turn mediates gene expression, e.g., between promoters and enhancers.
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