Biology Reference
In-Depth Information
capable of binding the retinoic acid receptor and functioning as RAREs in tran-
siently transfected cells (Vansant and Reynolds, 1995). We may thus surmise that
the random insertion of thousands of
Alu
sequences in the primate genome could
have altered the expression of numerous genes over evolutionary time.
An
Alu
sequence in the last intron of the human
CD8A
(2p12) gene operates so
as to modulate the activity of an adjacent T lymphocyte-specific enhancer
(Hambor
et al
., 1993). The
Alu
sequence appears to contain four functional tran-
scription factor binding sites [Lyf-1 (2), bHLH (1), GATA-3 (1)]. Hambor
et al
.
(1993) noted seven (non-CpG) nucleotide differences by comparing this
Alu
sequence with its probable source gene. Two of these differences were in the
GATA-3 binding site and both were shown by site-directed mutagenesis to be
necessary for its function (Hambor
et al
., 1993). This was therefore proposed to be
a possible example of positively selected change in an inserted
Alu
sequence.
However, since the
Alu
sequence appears to be capable of modulating the activity
of the enhancer through the formation of a cruciform (stem-loop) structure with
another downstream
Alu
sequence (Hanke
et al
., 1995), it is unclear what if any
role the putative binding sites might have in modulating enhancer activity.
An
Alu
sequence in the promoter region of the gene (
FCER1G
; 1q23) encoding
the gamma chain of the high affinity IgE receptor contains positive and negative
cis
-acting elements which contribute to the hematopoietic cell specificity of
expression of this gene (Brini
et al
., 1993). An
Alu
sequence in the myeloperoxi-
dase (
MPO
; 17q23.1) gene promoter contains four repeats related to the consen-
sus recognition sequence for nuclear hormone receptors (AGGTCA) (Piedrafita
et
al
., 1996). This sequence acts as a composite SP1-thyroid hormone-retinoic acid
response element interacting with SP1 as well as the retinoic acid and thyroid
hormone receptors (Piedrafita
et al
., 1996). An
Alu
sequence may also have been
recruited to perform a regulatory function in the human
1-globin gene (
HBQ1
;
16p13.3; Kim
et al
., 1989). Finally, the estrogen responsiveness of the human
breast cancer (
BRCA1
; 17q21) gene appears to have been conferred by an
Alu
repeat located within the promoter region of the gene (Norris
et al
., 1995).
Alu
sequences have thus introduced a variety of different DNA sequence motifs capa-
ble of binding a range of
trans
-acting factors that have altered the expression level
or tissue specificity of the associated genes.
Not all
Alu
sequences inserted into gene regions function as promoters or
enhancers of transcription. Indeed, an
Alu
sequence in the third intron of the
Wilms' tumor (
WT1
; 11p13) gene, 12 kb downstream of the promoter, acts as a
transcriptional silencer, repressing transcription of the
WT1
gene in cells of non-
renal origin (Hewitt
et al
., 1995). Since this silencer can function in an orienta-
tion- and distance-independent fashion, Hewitt
et al
. (1995) suggested that it may
have acquired silencer function rather than having simply possessed a silencer
function intrinsic to the
Alu
sequence. Another example of a silencer is the RRE
repetitive sequence element 1 kb upstream of the murine erythropoietin receptor
gene (Youssoufian and Lodish, 1993). This sequence, one of ~10
5
copies in the
mouse genome, may exert its
cis
-mediated repressor effect on the
EpoR
gene by
read-through transcription. Finally, a 27 bp sequence that is important in the neg-
ative regulation of a murine immunoglobulin
light chain gene appears to have
been derived from a B1 repetitive element (Saksela and Baltimore, 1993).
