FIG. 6.

HS core elements form a synergistic active subdomain within the LCR holocomplex. The figure depicts a cartoon of a model consistent with our data. (A) The LCR in the wild-type configuration. The core elements, together with the flanking regions, generate the holocomplex (light blue), with the core elements folded together to establish the specific configuration required for the active site (red). (B) Deletion of the HS2 core enhancer results in collapse of the LCR holocomplex and active site and renders the LCR unable to confer high-level or transgene integration position-independent transcription to the globin genes. (C) Deletion of the HS2 core element together with its flanking sequences allows the formation of an imperfect, alternative structure for the holocomplex, which retains transgene integration site-independent transcription but is impaired in its activity provided by the subdomain (light red). (D) Replacement of the HS2 by the HS3 core element allows the formation of an essentially wild-type holocomplex (thus retaining position-independent transcription of the integrated transgenes), but the active site is again unable to stimulate all the different globin genes at each developmental stage because it (light red) is not perfectly re-formed at each stage.