3D GENOMIC ORGANIZATION OF MOUSE MACROPHAGES

The spatial organization of the genome and its biological function are intimately linked. It is becoming evident that transcription regulation often involves multiple long-range regulatory elements and it’s influenced both by the genomic environment and by the shape of the genome. Recent studies based on Chromosome Conformation Capture-derived techniques, showed that eukaryotic cells organize their chromosomes into topological domains that are largely invariant among cell types and where the majority of looping interactions between regulatory elements take place (Dixon et al., 2012; Nora et al., 2012; Sexton et al., 2012). The principles defining the relationships between these elements and distal target genes remain poorly understood. Previous studies lack either the spatial resolution or the temporal coverage to observe possible dynamic changes in chromatin contacts between promoters and their corresponding distal regulatory elements during gene activation. Here we exploited high-resolution 4C and 5C techniques to elucidate principles of 3D organization of the macrophage genome, in both basal conditions and after macrophage activation, dissecting the specific role of the macrophage master regulator PU.1 in the formation of the general chromosome topology. Our findings indicate that the global organization of chromatin contacts is to a large extent unaffected by macrophage activation, which only partially impacts the looping between specific regulatory elements. Our analysis also reveals an high cell-type specificity of macrophage promoter-enhancer interactions, which is not dependent on the presence of PU.1.