Three phases in the dynamic activation of the HoxD locus are discussed further. (1) Condensationinitially, the cluster is in a condensed state (brown domain), covered by H3K27me3. It is relatively well insulated from T-DOM and its sub-TAD1 (although with constitutive contact points), except for a ~20-kb DNA fragment containing CBS1, which loops out toward the sub-TAD1 located CBS (CBS1, green double arrow). (2) Translocationwhile CBS1 keeps contacting the sub-TAD1 CBSs, Wnt-dependent transcriptional activation of anterior genes dissociates the cluster into two parts, with a now fully acetylated anterior domain where cohesin complexes will be preferentially loaded (blue domain). (3) Progressionactive loop-extrusion in this transcribed part will initially reach CBS1 as a first block, to subsequently reach CBS2 with a given frequency, thus activating Hoxd8 whose transcription will, in turn, recruit cohesin complexes, and hence a self-entertained mechanism will spread toward the posterior part, concomitantly to a retraction of the H3K27me3 domain.
