Blood, Vol. 93 No. 10 (May 15), 1999:
pp. 3540-3549
Analysis of Linked Human 
and 
Transgenes: Effect of Locus
Control Region Hypersensitive Sites 2 and 3 or a Distal YY1
Mutation on Stage-Specific Expression Patterns
Wei Zhu,
Catherine TomHon,
Marsha Mason,
Thomas Campbell,
Eric Shelden,
Neil Richards,
Morris Goodman, and
Deborah L. Gumucio
From the Department of Anatomy and Cell Biology, University of
Michigan, Ann Arbor, MI; Wallac, Inc, Akron, OH; Department of Anatomy
and Cell Biology, Wayne State University, Detroit, MI.
Stage-specific expression of the human 
-like globin genes is
controlled by interactions between regulatory elements near the
individual genes and additional elements located upstream in the Locus
Control Region (LCR). Elucidation of the mechanisms that govern these
interactions could suggest strategies to reactivate fetal (
) or
embryonic (
) genes in individuals with severe hemoglobinopathies. This study extends an earlier analysis of a transgenic construct, HS3, testing: (A) the effect of substitution of HS2 for HS3 on
stage-specific expression of the and genes and, (B) the role of
an evolutionarily conserved YY1 binding site in transcriptional regulation of the gene. The data show that both HS3 and
HS2 can individually support embryonic expression of and
fetal expression of A. Thus, the cis regulators of distinct
expression patterns for and are likely to reside near the
genes, rather than in specific hypersensitive sites of the LCR.
Alterations in A expression patterns observed in transgenic lines
carrying a construct with a mutation in a conserved YY1 binding site at
1086 indicate that this site might function to facilitate active
transcription of the gene in fetal life.
