Lessons from the analysis of TAD boundary deletions in normal population

Abstract

Topologically Associating Domains (TAD)-boundaries induce spatial constraints, allowing interaction between regulatory elements and promoters only within their TAD. Their disruption could lead to disease, through gene-expression deregulation. This mechanism has been shown in only a relatively low number of diseases and a relatively low proportion of patients, raising the possibility of TAD boundary disruption without phenotypical consequence. We investigated, therefore, the occurrence of TAD boundaries disruption in the general population. Coordinates of 307,430 benign deletions from public databases were crossed with 36 Hi-C datasets. Differences in gene content and gene localization were compared in the TADs, according to the possible disruption of their boundaries by a deletion found in the general population. TADs with no deletion encompassing their boundaries (R-TAD) represented 38% of TADs. Enrichment in OMIM genes as well as in morbid genes was observed in R-TADs and genes in R-TADs were found to localize closer to the boundaries.Our results support recent publications tempering the impact of breaking TADs on gene expression with a majority of broken TADs in the general population. A subgroup of R-TAD emerges from this analysis with enrichment in disease genes and their coordinates could be used to annotate CNV from pangenomic approaches to enhance data interpretation.

Enhancers in disease: molecular basis and emerging treatment strategies

“…However, while a large number of disease-related copy number variations (CNVs) are predicted to affect TAD structure [14,15], a whole-genome analysis in over 2500 cancer genomes identified almost 300 000 TAD disruptions, of which only 14% led to a change in gene expression [16]. Similarly, a recent study found that 41% of TADs across 36 datasets had at least one boundary disrupted by a common CNV classified as (likely) benign [17], indicating that TAD boundary deletion without a strong effect on the phenotype is widespread. Given the small numbers of diseases associated with a TAD boundary disruption, it appears that either such disruptions are too rare to be identified, too disruptive to produce a viable embryo, or not important enough to cause a detectable phenotype.…”

Toward an understanding of the relation between gene regulation and 3D genome organization

“…For example, the disruption of specificT A D boundaries or insulated structures and consequently unexpected enhancer-promoter interactions can induce aberrant gene expression, especially that of diseaserelated genes [7][8][9]. Surprisingly, the global loss of TAD structure via depletion of cohesin leads to significant changes of expression level of only about 1000 genes [10], indicating a limited role of TAD structure in regulating gene transcription [11]. Moreover, multiplex promoter-centered chromatin interactions such as promoter-promoter interactions of different genes have been widely investigated using ChIA-PET targeting on RNA polymerase II (RNAPII) and are thought to play a vital role in transcription regulation [12].…”