Evolution of Hox gene topologically-associating domains (TADs) by way of studying the amphioxus, one of the earliest chordates

Recently we have seen spectacu­lar progress in elucidating evolutionarily the 3-dimensional organization of the vertebrate genome and its impact on gene expression. In particular, genes controlling embryonic development have been found to be regulated by sets of remote cis-acting elements, heavily interacting with each other, and with gene promoters within the topologically-associated domains (TADs). In the report below (and editorial), authors present a new aspect to this research field––by reconstructing how such TADs arose during evolution.

A bilaterian is an animal having front and back, top and bottom (dorsal/ventral and anterior/posterior. For example, sponges and jelly fish do not have these properties and are therefore not bilaterians. This evolutionary divergence occurred during the “Cambrian Explosion” (about 542 million years ago). Acquisition of these properties is believed to be, in large part, due to the miraculous appearance of Hox (homeobox) genes. Invertebrates (animals not having a spine) generally carry only one Hox gene cluster, in zebrafish 42 Hox genes in five or six clusters, in humans and mice 39 HOX genes in four or more clusters.

Previous work has shown that vertebrate Hox gene clusters are regulated by two successive waves of transcriptional enhancement elicited from flanking genomic regions on opposing sides of the Hox clusters. The first wave includes early sequential expres­sion of Hox genes in the 3′ to 5′ direction, which is closely correlated with the anterior-to-posterior progression of development. This expression is essential for shaping embryonic axial tissues––including the proximal part of limb buds. Expression is controlled by enhancers spread over a large genomic domain abutting the Hox clusters on their 3′ (‘early’) side, forming an anterior regulatory landscape that has not been fully characterized to date.

The second wave of transcription concerns the 5′ Hox genes and is initiated on the other (‘late’) side of the HoxA and HoxD clusters, responding to well-characterized long-distance enhancers forming the posterior landscape. In the mouse, this latter regulation is functionally associ­ated with development of the most distal part of the limbs and the external genitalia. The HoxA and HoxD anterior-and-posterior regulatory landscapes in vertebrates were shown to correspond to anterior and poste­rior TADs, respectively.

 Authors in the attached fascinating paper … studied the origin of these chromatin TADs. Attempting to trace back existence of the Hox TADs earlier in evolution, authors performed a syntenic analysis to compare the organizations of genomic surround­ings of the Hox clusters in a number of inver­tebrates and chordates (earliest animals having spines), and in the vertebrates mouse and zebrafish. They found syntenic con­servation (order of genetic loci on same chromosome) exclusively between vertebrates and the cephalochordate amphioxus, an early-evolution animal that still exhibits many ancestral features of non-vertebrate chordates. These results imply that an interacting set of distant cis-acting elements––of the type involved in productive contacts with the Hox genes in vertebrates––can only be expected to be present in chordates (including mouse and human).

 Nat Genet  Mar 2o16; 48: 336–341 [article]  and  227–228 [editorial]


This entry was posted in Center for Environmental Genetics. Bookmark the permalink.