Biology Reference
In-Depth Information
trigger stimuli such as temperature, hormones and growth factors. In this way, gene
expression is rendered responsive to both the internal (cellular) and external (to the
organism) environment. Together, these upstream DNA sequences are involved in
controlling gene regulation and induction and conferring tissue-specificity of
expression (reviewed by Mitchell and Tjian, 1989).
A large number of DNA sequence motifs have now been identified within gene
promoters which represent binding sites for DNA-binding proteins (Johnson and
McKnight, 1989; Kel
et al
., 1995; see section 1.1.2,
Trans-acting protein factors
).
These protein-DNA interactions are required to confer appropriate regulation
upon the genes bearing them (reviewed by Clark and Doherty, 1993; Faisst and
Meyer, 1992; Freemont
et al
., 1991; Latchman, 1990). Removal of these DNA
sequence motifs abolishes the gene's specific pattern of spatial and/or temporal
expression.
Enhancers.
Enhancers are DNA sequences that are present 5
to a gene (or
within an exon or an intron) and which are capable of activating the transcription
of the gene in a tissue-specific fashion, independently of their orientation and dis-
tance from the correct initiation site (Müller
et al
., 1988; Wasylyk, 1988). Collins
et al
. (1998) reported the unusual case of the mouse thrombospondin 3 (
Thbs3
)
enhancer that is located far upstream of the
Thbs3
gene, within intron 6 of the
divergently transcribed metaxin (
Mtx
) gene.
Enhancers function by acting as templates for the assembly of multiprotein
complexes on the gene promoter. Thompson and McKnight (1992) likened
enhancer-protein interactions to a three-dimensional jigsaw puzzle:
or 3
'the arrangement of regulatory motifs forms the puzzle template. Specific reg-
ulatory proteins, by forming contours of appropriate fit for both DNA tem-
plate and neighbouring proteins, constitute the puzzle pieces.'
Mechanistic models involving the looping out of DNA between the enhancer and
the transcriptional initiation complex have been proposed in order to explain how
enhancers manage to influence the activity of their target promoters at consider-
able distances (Ptashne, 1988).
Negative regulatory elements.
The negative regulation of transcription by
repressors
or
silencers
is now so well documented (reviewed by Clark and Doherty,
1993; Herschbach and Johnson, 1993; Jackson, 1991; Levine and Manley, 1989)
that it is likely that many if not most genes are subject to their inhibitory influ-
ence. Indeed, every gene promoter region is likely to possess its own unique com-
bination of positive and negative regulatory elements which serves to determine
its temporal and spatial pattern of expression. These elements permit the binding
of a specific set of DNA-binding proteins which are thereby brought into suffi-
ciently close proximity so as to allow their interaction both with each other and
with the RNA polymerase in order to influence transcription either positively or
negatively. Negative regulation therefore serves to prevent the expression of a
gene in an inappropriate tissue or at an inappropriate time or at an inappropriate
level. They also potentiate the down-regulation of the expression of a gene fol-
lowing its transient induction. Negative regulatory elements have been found not
