Abstract:
:Deletions at the 3' end of the human beta-globin locus are associated with the hereditary persistence of fetal hemoglobin (HPFH) in adults, potentially through the juxtaposition of enhancer elements in the vicinity of the fetal gamma-globin genes. We have tested how sequences at the HPFH-2, HPFH-3, and HPFH-6 breakpoints, which act as enhancers in vitro, affect the silencing of a locus control region A gamma (LCRA gamma) transgene in the adult stage of mice. We found persistent A gamma expression in the adult blood of most of the multicopy HPFH-2, HPFH-3, or HPFH-6 lines, in contrast to the control LCRA gamma lines which were silenced. Cre-mediated generation of single copy lines showed persistent gamma gene expression maintained in some of the HPFH-2 and HPFH-6 lines, but not in any of the HPFH-3 or LCRA gamma lines. In the HPFH-2 and HPFH-6 lines, persistent gamma gene expression correlated with euchromatic transgene integrations. Thus, our observations provide support for a model whereby HPFH conditions arise from the juxtaposition of enhancers as well as permissive chromatin subdomains in the vicinity of the gamma-globin genes.
journal_name
Bloodjournal_title
Bloodauthors
Katsantoni EZ,Langeveld A,Wai AW,Drabek D,Grosveld F,Anagnou NP,Strouboulis Jdoi
10.1182/blood-2003-05-1681subject
Has Abstractpub_date
2003-11-01 00:00:00pages
3412-9issue
9eissn
0006-4971issn
1528-0020pii
2003-05-1681journal_volume
102pub_type
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