Biology Reference
In-Depth Information
merely in the promoter regions of human genes as in the
1-antitrypsin (
PI
;
14q32.1) gene (De Simone and Cortese, 1989) but also in the first exon [osteocal-
cin (
BGLAP
; 1q25-q31; Li
et al
., 1995) gene], the first intron [(
CD4
; 12pter-p12;
Donda
et al
., 1996) gene], or even the third intron [type IV collagen (
COL4A2
;
13q34; Haniel
et al
., 1995) gene] of a gene.
Locus control regions.
Regulatory elements that exert their effects on the expres-
sion of downstream genes over great distances have been described in the human
-
globin (
HBA1
; 16p13.3),
-globin (
HBB
; 11p15), growth hormone (
GH1
;
17q22-q24) and red/green cone pigment (
RCP
,
GCP
; Xq28) genes among others
(Hanscombe
et al
., 1991; Jarman
et al
., 1991; Jones
et al
., 1995; Wang
et al
., 1992;
Figure 6.2 in Chapter 6). These are known as
locus control regions
(LCRs). The LCR
located 40 kb upstream of the
HBB
gene is essential for the high level, tissue-spe-
cific expression of the
HBB
gene. It is believed to contain an enhancer capable of
controlling the replication timing of the
-globin gene cluster, organizing it into an
active chromatin domain and directing the expression of downstream sequences in
an erythroid-specific and developmental stage-specific fashion (Higgs, 1998;
Orkin, 1995). Although conserved between mammals, little homology is apparent
between mammalian and avian
-globin LCR regions (Hardison, 1998).
Trans
-acting protein factors.
As we have seen, the transcriptional activation of
eukaryotic genes is made possible by the interaction of
trans-
acting protein factors
with
cis
-acting DNA sequence motifs including enhancers. These transcription
factors typically contain a sequence-specific DNA-binding domain, a multimer-
ization domain which allows the formation of either homomultimers or hetero-
multimers, and a transcriptional activation domain. These domains can be
combined in modular fashion to generate an array of different transcription fac-
tors (Latchman, 1998; Tjian and Maniatis, 1994).
It is the
cis
-acting DNA sequences within a gene promoter that allow transcrip-
tion factors to be brought into close proximity so that they may either interact
with each other in the transcriptional initiation complex or combine together in
an enhancer complex. No one enhancer-binding protein can act on its own, rather
it must act in concert with other enhancer-binding proteins. For example, one
factor may induce a bend in the DNA thereby promoting the interaction of two
already bound proteins with each other. Once the enhancer complex is assembled,
it must be able to interact either directly or indirectly with the basal transcription
apparatus via its activation domain (Ptashne, 1988; Ptashne and Gann, 1990;
Pugh and Tjian, 1990).
Transcription factors can be grouped into families of related proteins whose
relatedness extends to homology in their DNA-binding domains and therefore an
ability to bind to related DNA sequences (reviewed by Pabo and Sauer, 1992).
Specific transcription factors can thus bind to more than one DNA sequence.
Conversely, a single DNA sequence motif may sometimes be bound by more than
one transcription factor. DNA-binding domains fall into one of four main groups
defined by homologous amino acid sequences that give rise to a particular struc-
ture capable of binding DNA: homeodomain, zinc finger, leucine zipper and
helix-loop-helix (Pabo and Sauer, 1992). These domains usually bind the negatively
