Constrained Transcriptional Polarity in the Organization of MammalianHoxGene Clusters
ABSTRACTIn many animal species with a bilateral symmetry,Hoxgenes are clustered either at one or at several genomic loci. This organization has a functional relevance, as the transcriptional control applied to each gene depends upon its relative position within the gene cluster. It was previously noted that vertebrateHoxclusters display a much higher level of genomic organization than their invertebrate counterparts. The former are always more compact than the latter, they are generally devoid of repeats and of interspersed genes, and all genes are transcribed by the same DNA strand, suggesting that particular factors constrained these clusters towards a tighter structure during the evolution of the vertebrate lineage. Here we investigate the importance of uniform transcriptional orientation by engineering several alleles within theHoxDcluster such as to invert one or several transcription unit(s), with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalianHoxclusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation ofHoxclusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulationviathe flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes incis.