Model illustrating how genome topology underlies the tissue-specific regulation of <i>HoxA</i> genes.

<p>The <i>HoxA</i> cluster is partitioned between two TADs (light blue), physically segregating <i>3′HoxA</i> from 5′<i>HoxA</i> genes in a mostly cell-type independent manner. In contrast, the sub-TAD interaction pattern is drastically different in the limb (<b>A</b>) compared to the head (<b>B</b>). Limb enhancer sub-TADs (dark blue) interact with each other and with gene-sub-TADs in distal limb but not head tissue. Enhancer and gene interactions occur between sub-TADs from the same TAD (5′<i>HoxA</i> containing TAD) but not with 3′<i>HoxA</i> genes that are located in the adjacent TAD. The limb-specific sub-TAD interactions create a platform architecture controlling <i>HoxA</i> expression by the remote distal limb enhancers upon enhancer activation by transcription factors. The schemes of the chromatin conformation were designed assuming cellular homogeneity within each tissue.