PT  - JOURNAL ARTICLE
AU  - Nurul Mubarokah
AU  - Julie-Ann Hulin
AU  - Peter I. Mackenzie
AU  - Ross A. McKinnon
AU  - Alex Z. Haines
AU  - Dong Gui Hu
AU  - Robyn Meech
TI  - Cooperative Regulation of Intestinal UDP-Glucuronosyltransferases 1A8, -1A9, and 1A10 by CDX2 and HNF4<em>α</em> Is Mediated by a Novel Composite Regulatory Element
AID  - 10.1124/mol.117.110619
DP  - 2018 May 01
TA  - Molecular Pharmacology
PG  - 541--552
VI  - 93
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/93/5/541.short
4100  - http://molpharm.aspetjournals.org/content/93/5/541.full
SO  - Mol Pharmacol2018 May 01; 93
AB  - The gastrointestinal tract expresses several UDP-glucuronosyltransferases (UGTs) that act as a first line of defense against dietary toxins and contribute to the metabolism of orally administered drugs. The expression of UGT1A8, UGT1A9, and UGT1A10 in gastrointestinal tissues is known to be at least partly directed by the caudal homeodomain transcription factor, CDX2. We sought to further define the factors involved in regulation of the UGT1A8-1A10 genes and identified a novel composite element located within the proximal promoters of these three genes that binds to both CDX2 and the hepatocyte nuclear factor (HNF) 4α, and mediates synergistic activation by these factors. We also show that HNF4α and CDX2 are required for the expression of these UGT genes in colon cancer cell lines, and show robust correlation of UGT expression with CDX2 and HNF4α levels in normal human colon. Finally, we show that these factors are involved in the differential expression pattern of UGT1A8 and UGT1A10, which are intestinal specific, and that of UGT1A9, which is expressed in both intestine and liver. These studies lead to a model for the developmental patterning of UGT1A8, UGT1A9, and UGT1A10 in hepatic and/or extrahepatic tissues involving discrete regulatory modules that may function (independently and cooperatively) in a context-dependent manner.