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Using Promoter Capture Hi-C data to understand evolution of expression regulatory landscapes in vertebrates  


Alexandre Laverré, LBBE  


Gene expression levels are regulated through complex molecular interactions, which involve multiple transcription factors and regulatory RNAs that bind to gene promoters and to distal regulatory elements, such as enhancers and repressors. Regulatory elements can be situated far from their target genes and chromatin loops bring them in contact with the gene promoters. The contacts between promoters and distant regulatory elements can now be explored at a genome-wide level thanks to the development of chromatin conformation capture techniques (3C, 4C, HiC and related approaches). Here, we use Promoter Capture Hi-C data, which specifically targets contacts between gene promoters and other genomic regions (Mifsud et al. 2015; Schoenfelder et al. 2015; Javierre et al. 2016). This novel technique allows us for the first time to analyse the evolution of regulatory landscapes with experimental data. We exploit the first genome-wide maps of promoter-chromatin contacts to perform a comparative analysis of expression regulatory landscapes in mouse and human. We show that the genomic sequences that are in contact with gene promoters are significantly conserved during evolution, even when located far from promoters. Despite differences in sampled cell types, we show that interactions are significantly conserved between the two species. Through comparisons with the complete genomes of several vertebrates, we observe that, at a broader evolutionary scale, the synteny between genes and contacted regions is signficantly conserved. We thus confirm that the structure of the regulatory landscapes, and in particular the presence of long-range regulatory interactions, constrain the large-scale evolution of vertebrate genomes. Key-words : Capture Hi-C, chromatin conformation, expression regulatory landscapes, genome evolution Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression

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