Chemistry Reference
In-Depth Information
Figure 6.2.
Transcription factor-binding sites of LCT proximal promoter in humans (adapted
from Troelsen, 2005). The transcription initiation codon is indicated in bold.
suggested to be involved in differentiation of the absorptive cells of the
intestinal epithelium (Mutoh et al., 2005) and has been shown to up-regulate
LCT expression in vitro. These observations would appear to support the
findings that Cdx-2 may regulate lactase expression at the brush border (Fang
et al., 2000).
The transcription factor HNF-1 is also known to modulate the expression
of lactase (Spodsberg et al., 1999; Krasinski et al., 2001; Bosse et al., 2006). One
HNF-1-binding site occurs in the proximalpromoterregion,andbothhuman
and pig promoters contain distal HNF-1 sites, although only the proximal site
shows conservation between the two species (Spodsberg et al., 1999). HNF-1
is
probably the main isoform binding the HNF-1 site (Spodsberg et al., 1999;
Bosse et al., 2006), and it has been shown that HNF-1
and Cdx-2 act synergis-
tically to activate lactase promoter activity in vitro (Mitchelmore et al., 2000).
The GATA-4/5/6 transcription factors have been shown to play a
critical role in the development of a number of endoderm-derived tissues, of
which the small intestine is one (reviewed by Burch, 2005), and they are also
implicated in the transcriptional regulation of a number of intestinally
expressed genes, including sucrase-isomaltase (Krasinski et al., 2001;
Boudreau et al., 2002), intestinal fatty acid-binding protein (Gao et al.,
1998) and trehelase (Oesterreicher and Henning, 2004), as well as lactase.
GATA-4, -5 and -6 all bind to a number of GATA recognition sites which
occur upstream of LCT, including two within the proximal promoter (Fitz-
gerald et al., 1998; Fang et al., 2001). It is thought that GATA-4 is the primary
GATA factor responsible for modulating LCT expression, due to the highly
correlated expression pattern of the two genes in small intestinal epithelia, in
combination with the observation that GATA-4 binding to the proximal
promoter is more evident than binding of either GATA-5 or -6 in EMSAs
using nuclear extracts prepared from mouse intestinal epithelia (van Wering
et al., 2004). Further to this, it has been shown that transgenic mice producing
an inducible mutant form of GATA-4 have significantly reduced LCT
