Τίτλος:
Persistent gamma-globin expression in adult transgenic mice is mediated
by HPFH-2, HPFH-3, and HPFH-6 breakpoint sequences
Περίληψη:
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
(LCR(A)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 LCR(A)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 LCR(A)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. (C) 2003 by The American Society of
Hematology.
Συγγραφείς:
Katsantoni, EZ
Langeveld, A
Wai, AWK
Drabek, D
Grosveld,
F
Anagnou, NP
Strouboulis, J
