Hepatocyte Nuclear Factor-1α, GATA-4, and Caudal Related Homeodomain Protein Cdx2 Interact Functionally to Modulate Intestinal Gene Transcription

Boudreau, François; Rings, Edmond H. H. M.; Wering, Herbert M. van; Kim, Richard K.; Swain, Gary P.; Krasinski, Stephen D.; Moffett, Jennifer; Grand, Richard J.; Suh, Eun Ran; Traber, Peter G.

doi:10.1074/jbc.m204622200

Cited by 216 publications

(252 citation statements)

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“…Cdx2 modulates cellular functions and intestine-specific gene expression (6,17,50,54). GATA-4 and HNF-1␣ are expressed in the intestinal epithelium and cooperate in transcriptional regulation of intestinal epithelial specific genes such as SI (6). Specific induction of these factors in differentiating IEC (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…HNF-1␣ was shown to participate in the transcriptional regulation of several intestinal specific genes (6,11,31,46,57,60). HNF-4␣ was recently suggested to act as a regulator of villus specific epithelial genes (53).…”

Section: Hnf-1␣ Is a Downstream Target Of Hnf-4␣ In Iec And Cooperatementioning

confidence: 99%

“…A number of regulators crucial to sustain the transcriptional activity of intestinal specific gene promoters have been identified (6,7,11,49,58). Characterization of the expression profile of some of these transcriptional modulators during the progression of the cocultures was next undertaken.…”

Section: Coculture Of Iec-6/l1 With Intestinal Mesenchymal Cells Resumentioning

confidence: 99%

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Hepatocyte nuclear factor-4α promotes differentiation of intestinal epithelial cells in a coculture system

Lussier

Babeu²,

Auclair³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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Normal cellular models able to efficiently recapitulate intestinal epithelial cell differentiation in culture are not yet available. The aim of this work was to establish and genetically characterize a mesenchymal-epithelial coculture system to identify transcriptional regulators involved in this process. The deposition of rat intestinal epithelial cells on human intestinal mesenchymal cells led to the formation of clustered structures that expanded shortly after seeding. These structures were composed of polarized epithelial cells with brush borders and cell junction complexes. A rat GeneChip statistical analysis performed at different time points during this process identified hepatocyte nuclear factor-4α (HNF-4α) and hepatocyte nuclear factor-1α (HNF-1α) as being induced coincidently with the apparition of polarized epithelial structures. Stable introduction of HNF-4α in undifferentiated epithelial cells alone led to the rapid induction of HNF-1α and several intestinal-specific markers and metabolism-related genes for which mRNA was identified to be upregulated during epithelial differentiation. HNF-4α was capable to transactivate the calbindin 3 gene promoter, a process that was synergistically increased in the presence of HNF-1α. When HNF-4α-expressing cells were plated on mesenchymal cells, an epithelial monolayer formed rapidly with the apparition of dome structures that are characteristics of vectorial ion transport. Forced expression of HNF-1α alone did not result in dome structures formation. In sum, this novel coculture system functionally identified for the first time HNF-4α as an important modulator of intestinal epithelial differentiation and offers an innovative opportunity to investigate molecular mechanisms involved in this process.

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Section: Discussionmentioning

confidence: 99%

Section: Hnf-1␣ Is a Downstream Target Of Hnf-4␣ In Iec And Cooperatementioning

confidence: 99%

Section: Coculture Of Iec-6/l1 With Intestinal Mesenchymal Cells Resumentioning

confidence: 99%

See 1 more Smart Citation

Hepatocyte nuclear factor-4α promotes differentiation of intestinal epithelial cells in a coculture system

Lussier

Babeu²,

Auclair³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…FireXy luciferase reporter plasmids carrying promoters of the diVerentiation markers lactase-phlorizin hydrolase (pGL3-LPH1085-13910T) (Troelsen et al 2003), intestinal alkaline phosphatase (pALPI_566) (Olsen et al 2005) and sucrase-isomaltase (pSI-202/+54) (Boudreau et al 2002) have been characterized elsewhere. The dipeptidyl peptidase IV (DPPIV) promoter plasmid was generated in our lab by PCR-ampliWcation of 1,382 bp of the immediate 5Ј promoter of DPPIV (sense primer: 5Ј-CGGGGTACCTTGGAAGA GGGAGGAGGAG-3Ј, antisense primer: 5Ј-GAAGATCT AGTCACTCGCCGCTGGCA-3Ј) followed by KpnI and BglII (underlined sequences) mediated insertion into pGL3, yielding the plasmid pGL3/Prom.dppIV.…”

Section: Plasmids and Plasmid Constructionmentioning

confidence: 99%

Differential expression of the integrins α6Aβ4 and α6Bβ4 along the crypt–villus axis in the human small intestine

Dydensborg

Teller

Basora

et al. 2008

Histochem Cell Biol

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The integrin 6 subunit exists as two diVerent variants, termed 6A and 6B. These two variants have been shown to harbor potentially distinct biochemical properties but little is known about their cellular function. The aim of this work was to characterize the expression of the integrin 6A and B variants in relation to cell proliferation and diVerentiation in the human small intestinal epithelium. The results showed distinct expression patterns for the two variants along the crypt-villus axis. Indeed, proliferative cells of the crypt were found to predominantly express 6A, while diVerentiated enterocytes and Paneth cells expressed the 6B variant. A similar relationship was observed in intestinal cell models by competitive RT-PCR. Further studies in the Caco-2 cell model showed that manipulating the cellular balance of the two 6 variants can inXuence transcriptional activities related to cell proliferation but not diVerentiation. This suggests that diVerential expression of the 6 subunits is involved in the intestinal epithelial cell renewal process. Further studies will be needed to substantiate this hypothesis.

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“…Semiquantitative real-time PCR was performed to determine sucrase and lactase mRNA levels and assess whether decreases in enzyme quantity were due to an inability to manufacture membrane-bound glycoproteins or attributable to mechanisms that specifically control levels of disaccharidase gene expression. Finally, mRNA levels for activators of sucrase and lactase gene expression caudal-related homeobox (CDX)-2, GATA-binding protein (GATA)-4, and hepatocyte nuclear factor (HNF)-1 (3,26,37) and the repressor pancreatic duodenal homeobox (PDX)-1 (15,39) were measured to gain insight into possible mechanisms by which any alterations in gene expression may be regulated by iron deficiency.…”

mentioning

confidence: 99%

Decreased sucrase and lactase activity in iron deficiency is accompanied by reduced gene expression and upregulation of the transcriptional repressor PDX-1

West¹,

Oates²

2005

American Journal of Physiology-Gastrointestinal and Liver Physi

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West, Adrian R., and Phillip S. Oates. Decreased sucrase and lactase activity in iron deficiency is accompanied by reduced gene expression and upregulation of the transcriptional repressor PDX-1. Am J Physiol Gastrointest Liver Physiol 289: G1108 -G1114, 2005. First published August 4, 2005; doi:10.1152/ajpgi.00195.2005.-Disaccharidases are important digestive enzymes whose activities can be reduced by iron deficiency. We hypothesise that this is due to reduced gene expression, either by impairment to enterocyte differentiation or by iron-sensitive mechanisms that regulate mRNA levels in enterocytes. Iron-deficient Wistar rats were generated by dietary means. The enzyme activities and kinetics of sucrase and lactase were tested as well as the activity of intestinal alkaline phosphatase (IAP)-II because it is unrelated to carbohydrate digestion. mRNA levels of ␤-actin, sucrase, lactase, and the associated transcription factors pancreatic duodenal homeobox (PDX)-1, caudal-related homeobox (CDX)-2, GATA-binding protein (GATA)-4, and hepatocyte nuclear factor (HNF)-1 were measured by real-time PCR. Spatial patterns of protein and gene expression were assessed by immunofluorescence and in situ hybridization, respectively. It was found that iron-deficient rats had significantly lower sucrase (19.5% lower) and lactase (56.8% lower) but not IAP-II activity than control rats. Kinetic properties of both enzymes remained unchanged from controls, suggesting a decrease in the quantity of enzyme present. Sucrase and lactase mRNA levels were reduced by 44.5% and 67.9%, respectively, by iron deficiency, suggesting that enzyme activity is controlled primarily by gene expression. Iron deficiency did not affect the pattern of protein and gene expression along the crypt to villus axis. Expression of PDX-1, a repressor of sucrase and lactase promoters, was 4.5-fold higher in iron deficiency, whereas CDX-2, GATA-4, and HNF-1 levels were not significantly different. These data suggest that decreases in sucrase and lactase activities result from a reduction in gene expression, following from increased levels of the transcriptional repressor PDX-1.anemia; transcription; nutrition; pancreatic duodenal homeobox CARBOHYDRATES are a vitally important dietary component, and disaccharidases are an essential subset of digestive enzymes required for the terminal step of carbohydrate digestion (13). The enzymatic activity of each individual disaccharidase is influenced primarily by the dietary level of their corresponding substrate (2, 12), and, under normal conditions, this level of activity is controlled by the abundance of the mRNA encoding the proteins (12, 34). However, it has been shown on many occasions that dietary iron deficiency can cause a significant decrease in disaccharidase activity (2,4,5,9,16,20,31,38) and that this decrease is reversible by iron supplementation (9,20,38).It is unlikely that iron is directly required for disaccharidase activity (16) or that iron deficiency alters the kinetic properties of sucrase (5). In additio...

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Hepatocyte Nuclear Factor-1α, GATA-4, and Caudal Related Homeodomain Protein Cdx2 Interact Functionally to Modulate Intestinal Gene Transcription

Cited by 216 publications

References 57 publications

Hepatocyte nuclear factor-4α promotes differentiation of intestinal epithelial cells in a coculture system

Hepatocyte nuclear factor-4α promotes differentiation of intestinal epithelial cells in a coculture system

Differential expression of the integrins α6Aβ4 and α6Bβ4 along the crypt–villus axis in the human small intestine

Decreased sucrase and lactase activity in iron deficiency is accompanied by reduced gene expression and upregulation of the transcriptional repressor PDX-1

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