Submitted April 3, 2006
Accepted April 14, 2006
Flanking HS-62.5 and 3'HS1, and
regions upstream of the LCR are not required for 
-globin transcription
M A Bender*, Rachel Byron, Tobias Ragoczy, Agnes Telling, Michael Bulger, and Mark Groudine
Fred Hutchinson Cancer Research Center, Seattle, WA
Center for Pediatric Biomedical Research, University of Rochester, NY
* Corresponding author; email: mbender{at}fhcrc.org.
The locus control region (LCR) was thought to be
necessary and sufficient for establishing and
maintaining an open 
-globin locus chromatin
domain in the repressive environment of the developing
erythrocyte. However, deletion of the LCR from the
endogenous locus had no significant effect on chromatin
structure and did not silence transcription. Thus the
cis-regulatory elements that confer the open domain
remain unidentified. The conserved DNaseI
hypersensitivity sites (HSs) HS-62.5 and 3'
HS1 that flank the locus, and the region upstream
of the LCR have been implicated in globin gene
regulation. The flanking HSs bind CTCF and are thought
to interact with the LCR to form a " chromatin hub "
involved in -globin gene activation. Hispanic
thalassemia, a deletion of the LCR and 27kb upstream,
leads to heterochromatinization and silencing of the
locus. Thus the region upstream of the LCR deleted in
Hispanic thalassemia (UHR) may be required for
expression. To determine the importance of the UHR and
flanking HSs for -globin expression, we generated
and analyzed mice with targeted deletions of these
elements. We demonstrate deletion of these regions
alone, and in combination, do not affect transcription,
bringing into question current models for the regulation
of the -globin locus.
