Blood, 15 November 2002, Vol. 100, No. 10, pp. 3443-3443
Of mouse, not of man? a surprise at the 
-globin
locus
Cellular and transgenic models have provided important insights
into the molecular mechanisms required for mammalian globin gene
expression. The homology of the human and murine 
- and 
-promoter sequences coupled with in vivo transcriptional analysis suggested that
the genes were controlled in a similar manner in murine and human
erythroid cells. The identification of 4 upstream erythroid-specific DNaseI hypersensitive (HS) sites in both species confirmed the overall structural similarity of the -loci. Support for a
conservation of function was provided by the demonstration that some HS
sites enhance transcription significantly when linked with a globin promoter in cis. These studies resulted in a model in which
the sequences required for developmental-specific expression reside in
gene-proximal promoters, the upstream HS being required for high-level tissue-specific expression.
A key test of this model is provided by Anguita and colleagues
(page 3450), in which they determine the function of a key upstream HS
site at the endogenous murine -globin locus. Previous work by this
group using a chromosome 16 somatic hybrid cell line demonstrated that
disruption of hHS 
40, a single HS site located 40kb upstream of the
human -globin genes, resulted in complete loss of -globin gene
expression. In the present study, homologous disruption of the
apparently functionally equivalent murine HS site, mHS 26, was
performed with the expectation of a resultant severe -thalassemic
phenotype in animals homozygous for the deletion. In contrast to the
human studies, homozygotes have relatively normal erythropoiesis except
when subjected to anemia-inducing phenylhydrazine stress. This result
is reminiscent of similar studies deleting individual HS sites in the
murine 
-globin locus control region (LCR) (Bender et al, Mol Cell.
2000;5:387-393). Several potential explanations for the
species-specific difference in outcome can be entertained. These
include the unique telomeric location of the human locus when compared
to the interstitial position of its murine ortholog, a modest
divergence in factor binding sites between the mHS 26 and hHS 40
regions, and/or the confirmed differences in enhancer action of hHS
40 and mHS 26, as measured in murine erythroleukemia cells as
reported here. An equally attractive hypothesis, linking many of these
observations, is that 2 or more HS sites may be required for
appropriate murine -globin gene expression. In contrast, hHS 40
may be sufficient at the human locus. Further experimentation at the
endogenous loci will be required to distinguish these possibilities.
Indeed, it is likely that further Darwinian surprises are in store that will remind us that murine and human globin biology may not be one and
the same.
John M. Cunningham and Stephen M. Jane
St Jude Children's Research Hospital and Rotary Bone Marrow
Research
Laboratory
