Simple math for the β-globin locus control region

The only universally agreed upon property attributable to the locus control region (LCR) is its absolute requirement for elevated transcriptional activity of the vertebrate β-type globin genes. Previously, the Groudine group reported that targeted deletion of hypersensitive sites (HSs) 2, 3, or 5/6 from the LCR affected the level, but not the developmental timing, of globin gene transcription. Here, Bender and colleagues (page 2022) report deletions of the final 2 murine β-globin LCR HSs, HS1 and HS4, thus closing one chapter in this saga. Because the mouse has 2 genetically distinguishable alleles (Hbb^S and Hbb^D), the wild-type allele serves as an internal control for nicely distinguishing quantified expression of the mutant. Additionally, since mutation of the endogenous locus cannot suffer from position of integration effects (as can transgenes), analysis of mutant expression leads to clear assessment of the transcriptional activity from individual HS loss of function. The data show that deletion of HS1 or HS4 reduces adult (definitive) gene transcription by approximately 20%, while there is little effect on embryonic transcription. In summarizing the results of all individual murine LCR HS deletions, Bender and colleagues conclude that each HS site contributes additively to LCR transcriptional stimulatory function.

But there is almost certainly another chapter to follow. Bender and colleagues' conclusions are in marked contrast to the inferences from some transgenic human β-globin locus studies, which suggest that the LCR stimulates transcription as a synergistic holocomplex. As reviewed in the paper, these contrasting conclusions could arise from transspecies issues (human genes expressed in the mouse; possible), from position of integration effects (likely), or from the nature and extent of the different mutations that have been examined to date (also likely). Aspects of these potential complications may be resolved by examining finer mutations in the endogenous locus, since the basis for a synergistic LCR model was established by examining small deletions in human β-globin YAC transgenes, in contrast to the larger targeted deletions such as those reported here.