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.
Highlights
Vertebrate limbs have been a paradigm in our understanding of the emergence of patterns during evolution and development, in terms of both the molecules involved and the underlying principles
The HoxD cluster is flanked by two large gene deserts (TDOM and C-DOM), which match the extent of two topologically associating domains (TADs) (Fig. 1A; Dixon et al 2012)
The telomeric T-DOM contains at least two enhancers (CS39 and CS65), which regulate the transcription from Hoxd8 to Hoxd11 into a proximal limb domain (Andrey et al 2013)
Summary
Vertebrate limbs have been a paradigm in our understanding of the emergence of patterns during evolution and development, in terms of both the molecules involved and the underlying principles (e.g., see Tabin and Wolpert 2007). The existence of two separate and independent regulatory landscapes allows for the appearance of a stripe of nonexpressing cells between the two transcript domains These cells express low levels of Hox genes and are thought to produce the mesopodial articulation; i.e., the wrist and ankle (Villavicencio-Lorini et al 2010; Woltering and Duboule 2010). In this context, the switch in TAD regulations is key in the making and positioning of the mesopodium, an essential structure in the evolution of tetrapods, which allowed them to properly articulate their newly acquired digits
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