Abstract
BackgroundOur understanding of the nuclear chromatin structure has increased hugely during the last years mainly as a consequence of the advances in chromatin conformation capture methods like Hi-C. The unprecedented resolution of genome-wide interaction maps shows functional consequences that extend the initial thought of an efficient DNA packaging mechanism: gene regulation, DNA repair, chromosomal translocations and evolutionary rearrangements seem to be only the peak of the iceberg. One key concept emerging from this research is the topologically associating domains (TADs) whose functional role in gene regulation and their association with disease is not fully untangled.ResultsWe report that the lower the number of protein coding genes inside TADs, the higher the tendency of those genes to be associated with disease (p-value = 4 × 10^{-54}). Moreover, housekeeping genes are less associated with disease than other genes. Accordingly, they are depleted in TADs containing less than three protein coding genes (p-value = 3.9 × 10^{-34}). We observed that TADs with higher ratios of enhancers versus genes contained higher numbers of disease-associated genes. We interpret these results as an indication that sharing enhancers among genes reduces their involvement in disease. Larger TADs would have more chances to accommodate many genes and select for enhancer sharing along evolution.ConclusionsGenes associated with human disease do not distribute randomly over the TADs. Our observations suggest general rules that confer functional stability to TADs, adding more evidence to the role of TADs as regulatory units.
Highlights
Our understanding of the nuclear chromatin structure has increased hugely during the last years mainly as a consequence of the advances in chromatin conformation capture methods like Hi-C
Thanks to the high resolution of the Hi-C data set, we were able to detect an abrupt enrichment of transcription starting sites (TSSs) within topologi‐ cally associating domains (TADs) from the borders up to a distance of − 4500 nt (Fig. 1; [12]), as well as the already known housekeeping genes (HKs) bias toward TAD borders (Additional file 1: Figure S1; p-value = 3 × 10−4, Wilcoxon rank test)
The fact that genes near TAD borders are less associated with disease is in agreement with the preference of loci of HK for TAD borders: HK genes are less associated with disease than nonHK genes (30.9% and 36.6%, respectively; Table 1, p-value = 1.67 × 10−10 )
Summary
Our understanding of the nuclear chromatin structure has increased hugely during the last years mainly as a consequence of the advances in chromatin conformation capture methods like Hi-C. The unprecedented resolution of genome-wide interaction maps shows functional consequences that extend the initial thought of an efficient DNA packaging mechanism: gene regulation, DNA repair, chromosomal translocations and evolutionary rear‐ rangements seem to be only the peak of the iceberg. Chromatin structure is a key factor in many biological functions like transcription, chromosome translocations, DNA repair and replication [1]. Chromosome conformation capture (3C) detects close genomic regions (three dimensional space) by proximity ligation using formaldehyde-mediated cross-linking [10]. Those loci-captures are quantified by means of a sequencing technology, determining the technology variant (4C, 5C, Hi-C and ChIA-PET). The Hi-C data provided from Rao et al on Human GM12878 cells [13] reached a resolution of less than 1 Kbp, at the cost of 4.9 billions reads for a single experiment
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