The distributions of protein coding genes within chromatin domains in relation to human disease

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 × ). 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 × ). 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.

Making sense of the linear genome, gene function and TADs

“…This suggests that genes in TADs on their own are less tolerant to mutation and therefore more functionally important. This is supported by Muro et al [ 39 ] who recently found that genes which singly occupy a TAD are more likely to be associated with disease. We analysed the functional enrichment of the genes singly occupying TADs and found a strong enrichment for developmental processes.…”

“…Using bedtools intersect [ 47 ], protein-coding genes were overlapped and assigned to a TAD if their start and end position fell within the same TAD. This TAD-gene mapping method is more stringent than previously used [ 17 , 18 , 39 ], but it allows us to focus on genes which can be confidently assigned to a TAD and controls for the possibility that genes which overlap a TAD boundary may have different features. This is especially important given recent evidence has shown that TAD boundaries are often not “sharp”, instead boundaries can span “zones of transition” meaning that it may not be possible to confidently assign genes spanning a TAD boundary to one TAD or the other [ 48 ].…”

Making sense of the linear genome, gene function and TADs

“…This suggests that genes in TADs on their own are less tolerant to mutation and therefore more functionally important. This is supported by Muro et al (33) who recently found that genes which singly occupy a TAD are more likely to be associated with disease. When we separated TADs into CTCF TADs and non-CTCF TADs we found that this relationship is stronger for CTCF TADs compared to non-CTCF TADs (Supplementary figure 6).…”

“…Using bedtools intersect (40), protein coding genes were overlapped and assigned to a TAD if their start and end position fell within the same TAD. This TAD-gene mapping method is more stringent than previously used (16,17,33) but it allows us to focus on genes which can be confidently assigned to a TAD and controls for the possibility that genes which overlap a TAD boundary may have different features. This is especially important given recent evidence has shown that TAD boundaries are often not "sharp", instead boundaries can span "zones of transition" meaning that it may not be possible to confidently assign genes spanning a TAD boundary to one TAD or the other (41) In order to assess the functional similarity between pairs of genes in TADs, unless otherwise stated olfactory genes were removed from analysis.…”

Epigenetics and Heart Development

“…Disruption of TADs during development is implicated in ectopic gene expression and disease ( Ibn-Salem et al, 2014 ; Lupianez et al, 2015 , 2016 ; Muro et al, 2019 ). Comparison of genome architecture in primate, mouse, cattle, opossum, chicken, clawed frog, and zebrafish showed conservation of non-coding regions that coincide with TAD boundaries ( Harmston et al, 2017 ; Krefting et al, 2018 ).…”