The constrained architecture of mammalian Hox gene clusters

Abstract

In many animal species with a bilateral symmetry, Hox genes 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 vertebrate Hox clusters 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 toward a tighter structure during the evolution of the vertebrate lineage. Here, we investigate the importance of uniform transcriptional orientation by engineering several alleles within the HoxD cluster, such as to invert one or several transcription units, with or without a neighboring CTCF site. We observe that the association between the tight structure of mammalian Hox clusters and their regulation makes inversions likely detrimental to the proper implementation of this complex genetic system. We propose that the consolidation of Hox clusters in vertebrates, including transcriptional polarity, evolved in conjunction with the emergence of global gene regulation via the flanking regulatory landscapes, to optimize a coordinated response of selected subsets of target genes in cis.

Nucleoporin 153 links nuclear pore complex to chromatin architecture by mediating CTCF and cohesin binding

“…This analysis has also revealed that NUP153 associates with several Hox genes, which are characterized as bivalent genes in mouse ES cells 1,48 . Genomic organization of the Hox loci relies on TADs with enriched CTCF binding 44 and influences developmental expression of Hox genes 49 . As presented in the representative tracks shown for the HoxA and HoxC clusters, we found that NUP153 depletion resulted in altered CTCF and/or cohesin binding at specific Hox genes (Fig.…”

The origin of animal body plans: a view from fossil evidence and the regulatory genome

“…The origin of TADs has been accompanied by increased clustering of coexpressed developmentally related genes, allowing these syntenic blocks to be regulated as a unit (Heger et al, 2012). Vertebrates, for example, exhibit clustering of Hox genes (Darbellay et al, 2019); however, by the time of origin of hemichordates, four transcription factor genes (nkx2.1, nkx2.2, pax1/9 and foxA) had assembled into a microsyntenic group (the pharyngeal cluster) controlling development of the pharyngeal 'gill' slits (Simakov et al, 2015).…”

A complex regulatory landscape involved in the development of mammalian external genitals

“…While such negative ground-state structures may simply reflect the absence of upstream factors and/or represent a scaffold to reinforce future enhancer-promoter contacts (Paliou et al, 2019), it may in our case be functionally required to prevent any transcriptional leakage of Hoxd13. HOX13 products are indeed potent dominant negative proteins (Darbellay et al, 2019;Villavicencio-Lorini et al, 2010) and their ectopic production in time and space must be prevented for proper development to be achieved (e.g. (Young et al, 2009).…”