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to the transcriptional initiation site
of the human parathyroid hormone ( PTH ; 11p15.1-p15.3) gene, contributes
toward a negative calcium response element (McHaffie and Ralston, 1995;
Okazaki et al ., 1991). This element possesses a 12 bp palindromic core ( TGA-
GAC AGG GTCTCA ) and since it is common in the human genome courtesy of
the wide distribution of Alu sequences, it may have provided the means for the
expression of other genes to be down-regulated by extracellular calcium.
Wu et al . (1990) have proposed that an Alu repeat 2.2 kb upstream of the human
A motif within an Alu sequence, 3.6 kb 5
-globin ( HBE1 ; 11p15.5) gene abolishes down-regulation of the gene mediated
by a silencer element 4.5 kb upstream. These authors suggested that the down-
regulation was caused by transcriptional interference and that the Alu repeat
somehow blocks transcription from the upstream element specifically in embry-
onic erythroid cells where it is transcriptionally active.
Upon insertion, Alu sequences may also provide alternative sites for transcrip-
tional initiation, as found in the human apolipoprotein B mRNA-editing enzyme
( APOBEC1 ) gene (12p13.1; Fujino et al ., 1998). The human APOBEC1 gene is
expressed exclusively in the small intestine whereas in rodents, the gene is more
widely expressed. Whilst the human gene contains two Alu sequences and two
major transcriptional initiation sites, its murine counterpart lacks Alu repeats and
contains a single transcriptional initiation site ( Figure 5.6 ). Insertion of the Alu
sequences must therefore have occurred during the last 100 Myrs since the diver-
gence of the primate and rodent lineages. In the human gene, the first Alu repeat
contains the first of the transcriptional initiation sites and lies upstream of a
region exhibiting strong homology to the murine intestinal promoter. The second
Alu repeat contains the second transcriptional initiation site and is located in the
first intron. Comparison with the murine gene suggests that Alu sequence inser-
tion may have split the human intestinal promoter leading to utilization of the
downstream Alu sequence as an alternative site of transcriptional initiation. In
this case, it would appear as if promoter function has simply adapted to the pres-
ence of the Alu repeat rather than being qualitatively altered by it.
Endogenous retroviral elements. Not all inserted sequences implicated in
influencing gene expression are Alu repeats. One example of the recruitment of
ATG
Human
Exon1
Exon2
Alu sequence
Alu sequence
68.6
ATG
Mouse
Exon4
+I
-1500
-1000
-500
-250
Figure 5.6. Comparison of human and mouse APOBEC1 gene promoters (from Fujino et
al. , 1998). Transcriptional initiation sites are denoted by vertical arrows. Alu sequences
are denoted by horizontal arrows. The murine exon 4 is homologous to a portion of
human exon 2. The region of transcriptional initiation between nucleotides -848 and -
1034 of the human gene is ~70% homologous to the region of the murine gene promoter
responsible for intestinal expression.
 
 
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