Impact of copy number variations (CNVs) on long-range gene regulation at the HoxD locus

Abstract

Copy number variations are genomic structural variants that are frequently associated with human diseases. Among these copy number variations, duplications of DNA segments are often assumed to lead to dosage effects by increasing the copy number of either genes or their regulatory elements. We produced a series of large targeted duplications within a conserved gene desert upstream of the murine HoxD locus. This DNA region, syntenic to human 2q31-32, contains a range of regulatory elements required for Hoxd gene transcription, and it is often disrupted and/or reorganized in human genetic conditions collectively known as the 2q31 syndrome. Unexpectedly, one such duplication led to a transcriptional down-regulation in developing digits by impairing physical interactions between the target genes and their upstream regulatory elements, thus phenocopying the effect obtained when these enhancer sequences are deleted. These results illustrate the detrimental consequences of interrupting highly conserved regulatory landscapes and reveal a mechanism where genomic duplications lead to partial loss of function of nearby located genes.chromatin architecture | enhancer-promoter interaction

Gene regulation at a distance: From remote enhancers to 3D regulatory ensembles

“…Interestingly, the regulatory properties of these regulatory ensembles are in part dictated by the relative distribution of the different modules and of their target gene on the genome [41,137], showing again the influence of the structural organization on the regulatory output.…”

Deletions, Inversions, Duplications: Engineering of Structural Variants using CRISPR/Cas in Mice

“…Furthermore, it was shown that SVs could interfere with gene regulation by disrupting genomic architecture necessary for proper enhancer-promoter interactions. Such rearrangements can result in loss of WT interactions and/or ectopic enhancer-promoter interactions, thereby resulting in gene misexpression (Montavon et al, 2012;Spielmann et al, 2012;Spielmann and Mundlos, 2013). To discriminate between these multiple effects and to study their complex molecular pathology in vivo modeling of SVs is required.…”

Characterization of hundreds of regulatory landscapes in developing limbs reveals two regimes of chromatin folding

“…4C requires much less sequencing to achieve a high resolution but limits the analysis to a single viewpoint. Because of its high resolution and low production cost, 4C has been extensively used to explore the regulatory microarchitecture of specific loci and as a proxy to recapitulate and assess TADs structure and variability (Montavon et al 2012;Andrey et al 2013;Ghavi-Helm et al 2014;Lupianez et al 2015;Acemel et al 2016).…”