A role for HOX13 proteins in the regulatory switch between TADs at the HoxD locus

Abstract

During vertebrate limb development, Hoxd genes are regulated following a bimodal strategy involving two topologically associating domains (TADs) located on either side of the gene cluster. These regulatory landscapes alternatively control different subsets of Hoxd targets, first into the arm and subsequently into the digits. We studied the transition between these two global regulations, a switch that correlates with the positioning of the wrist, which articulates these two main limb segments. We show that the HOX13 proteins themselves help switch off the telomeric TAD, likely through a global repressive mechanism. At the same time, they directly interact with distal enhancers to sustain the activity of the centromeric TAD, thus explaining both the sequential and exclusive operating processes of these two regulatory domains. We propose a model in which the activation of Hox13 gene expression in distal limb cells both interrupts the proximal Hox gene regulation and re-enforces the distal regulation. In the absence of HOX13 proteins, a proximal limb structure grows without any sign of wrist articulation, likely related to an ancestral fish-like condition.

Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape

“…S6D). The latter had been previously described as an enhancer driving Hoxd expression in developing limb buds (17,52). Immediately 5′ of CS39, we identified a ca.…”

“…This particular DNA region maps at the boundary between two sub-TADs within the T-DOM (17) (Fig. 5A), and chromosome conformation capture approaches have revealed its strong contacts with the HoxD gene cluster in either transcriptionally active or inactive cellular contexts (17,18,23,52). Of note, the interactions observed between this DNA region and Hoxd9 are usually stronger than with the other Hoxd genes (Fig.…”

Integration of Shh and Fgf signaling in controlling Hox gene expression in cultured limb cells

“…Alternatively, it is possible that, under these conditions, Hoxd13 expression was controlled by enhancers localized within T-DOM. Although this does not seem to normally occur in vivo, at least with a high efficiency (24), T-DOM enhancers were shown recently to have this capacity in the absence of both Hoxd13 and Hoxa13 products (25). Therefore, in our in vitro system, we cannot rule out the possibility that the amounts of HOX13 products may not be high enough to implement the regulatory switch.…”

“…The successive implementation of phase I and phase II Hoxd gene regulations in the limb bud depends upon two distinct and opposite regulatory landscapes, matching topologically associating domains (TADs) (24,25). In the incipient limb bud, Hoxd9, Hoxd10, and Hoxd11 transcription is controlled by T-DOM, a regulatory landscape containing several enhancers with a proximal specificity.…”

“…Phase I expression depends on contacts with the telomeric regulatory landscape, whereas phase II transcription depends upon enhancers located in the centromeric landscape (23,24). The switch between these distinct regulations is at least partially dependent upon the activity of the Hoxd13 and Hoxa13 genes (25).…”