Convergent evolution of cluster-wide Hox gene regulation in Bilateria

Abstract

The anteroposterior collinear expression of Hox genes is a hallmark of animal development that underpins the diversification of body plans1 and life cycles2. However, the origin and drivers of this coordinated expression remain elusive: while vertebrates rely on complex cluster-wide Hox gene regulation3-8, insects define gene-specific, sub-cluster regulatory domains9-11. Here, we discover a new mode of Hox gene regulation in segmented worms (Annelida). By combining chromatin conformation data with histone modifications profiling in Owenia fusiformis, we show that a large distal enhancer forms developmentally regulated, long-range contacts across the Hox cluster, and its activation coincides with the consolidation of a cluster-wide topologically associating domain (TAD), loss of Polycomb-mediated repression, and Hox gene transcription. This chromatin structure also occurs in the annelids Dimorphilus gyrociliatus and Capitella teleta, the latter showing additional subTAD structures that correlate with Hoxs temporal collinearity12. Moreover, related phyla with intact, organised Hox clusters and spatial collinearity, such as nemerteans and chitons, show annelid-like chromatin organisations, whereas phyla with disorganised13 Hox clusters do not. Coordinated Hox gene regulation from a "global control region" is thus ancestral to Lophotrochozoa, indicating that complex regulatory logics based on cluster-wide, long-range chromatin interactions with distal enhancers evolved convergently in vertebrates and spiralians.