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. 2017 Jul 15;31(14):1406–1416. doi: 10.1101/gad.303123.117

Figure 4.

Figure 4.

Two temporal sequences in Hoxd gene activation during limb bud development. (A) Limb phase 1. HoxD in the early bud is controlled (green arrow) exclusively by enhancers located in the 3′ TAD. Time sequence of Hoxd activation (t1 to t11) is the same as in the trunk (Fig. 1), and the nested expression domains generated occupy the proximal part of the E12.5 limb bud (right limb bud) and pattern the long bones along with genes from the HoxA cluster. Arrows are transcriptionally active genes, corresponding to open chromatin. (B) Limb phase 2. Between 24 and 48 h after the start of phase 1, enhancers in the 5′ TAD are switched on and activate Hoxd10 to Hoxd13 (purple arrow). HOX13 products then switch off the 3′ TAD enhancers in cells located at the posterior-distal margin. These cells expand and generate the autopods (hands and feet). (C) Combination of limb phases 1 and 2. The 3′ and 5′ TADs operate sequentially, leaving a zone of low Hox expression as the limb bud grows distally, which generates the future mesopods (wrist and ankle). Anterior is to the top, and distal to the right. The color code for Hox gene expression is the same as in Figure 1.