Blood, 1 October 2001, Vol. 98, No. 7, pp. 2000-2000
Simple math for the 
-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 
-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 -globin LCR HSs, HS1 and HS4, thus closing one chapter in
this saga. Because the mouse has 2 genetically distinguishable alleles
(HbbS and HbbD), 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 -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 -globin YAC
transgenes, in contrast to the larger targeted deletions such as those
reported here.
James Douglas Engel
Northwestern
University
