Biology Reference
In-Depth Information
expression profiles. Steroid hormone receptor responsive elements (Chapter 7,
section 7.5.2,
The DNA-binding specifiicity of steroid receptors
) are a classic example
of this but a number of other studies of paralogous gene promoters have been
reported which serve to illustrate the basic principles.
The murine immunoglobulin variable region heavy chain (V
H
) genes may be
grouped into 15 families on the basis of coding sequence homology, and the pro-
moter sequences are conserved in a family-specific manner (Buchanan
et al
.,
1997). However, these paralogous V
H
gene promoters vary in terms of their tran-
scriptional strength, at least
in vitro
, by as much as 60 to 70-fold. This variation
appears to be due to several specific sequence differences between these promot-
ers: (i) the presence/absence of a TATA box, (ii) the presence/absence of initiator
elements, (iii) the extent of divergence of the octamer sequence element from its
consensus (ATGCAAAT), and (iv) the spacing between the octamer motif and the
heptamer motif located between 2 bp and 20 bp upstream (Buchanan
et al
., 1997).
The human genome contains a cluster of 11 pregnancy-specific glycoprotein
(
PSG
) genes on the long arm of chromosome 19q (
PSG1
,
PSG2
,
PSG3
,
PSG4
,
PSG5
,
PSG6
,
PSG7
,
PSG8
,
PSG11
,
PSG12
,
PSG13
). These genes are highly
homologous and this homology extends to their promoter regions. The promoters
of six
PSG
genes have been characterized and display differences based upon the
minimal promoter required for optimal expression (Chamberlin
et al
., 1994). The
class 1
PSG
genes require nucleotides
34 (relative to the transcriptional
initiation site) whereas the comparable minimal region of class 2
PSG
genes lies
between
172 to
80. This difference has been attributed to the presence of an
imperfect SP1 binding site between
172 and
141 in the class 1 promoters. The
perfect SP1 element (CCCCGCCC) present in the class 2 promoters is altered
either to CCCTGCCC or CCCCACCC (NB. both represent mutations in a CpG
dinucleotide compatible with the mechanism of methylation-mediated deamina-
tion) in the class 1 promoters (Chamberlin
et al
., 1994). The SP1 binding sites of
the class 1 promoters bind SP1 with lower affinity and require additional activa-
tor elements for optimal expression (Chamberlin
et al
., 1994).
One of the best characterized differences between paralogous gene promoters is
that manifested by one of the human small proline-rich protein genes. The
SPRR1A
,
SPRR1B
,
SPRR2A,
and
SPRR2C
genes possess an Ets binding site at
position
148 and
55 (relative to the transcriptional initiation sites) which is critical for
promoter activity. The corresponding site in the
SPRR3
gene has however been
lost through a C
T transition, although this loss appears to be compensated for,
at least in part, by the presence of an Ets binding site at position
239 (Fischer
et
al
., 1999). This single base-pair substitution has been shown to account for the
lower rate of expression of the
SPRR3
gene in cultured keratinocytes as compared
with the
SPRR1A
and
SPRR2A
genes. This is despite the fact that the
239 Ets
binding site in the
SPRR3
gene has a higher affinity for its cognate transcription
factor ESE-1 than the
55 sites in the
SPRR1A
and
SPRR2A
gene promoters.
Fischer
et al
. (1999) found that removal of the
239 Ets binding site coupled with
the restoration of the
C mutation yielded a promoter
activity comparable to that of the
SPRR1A
and
SPRR2A
promoters and three-
fold higher than that of the wild-type
SPRR3
promoter. The location of the Ets
binding site in the
SPRR3
gene therefore appears to be critical for determining
55 binding site by a T
