title: Forkhead box transcription factors Foxa1 and Foxa2 are important regulators of Muc2 mucin expression in intestinal epithelial cells.
abstract: The mucin Muc2 is the main component of the intestinal mucus layer and thus plays important roles in intestinal protection. Therefore, it is important to understand its regulation during goblet cell differentiation. Foxa1 and Foxa2 forkhead box transcription factors (TFs) participate in transcriptional programs governing intestinal cell differentiation. Using immunohistochemistry, we showed a spatio-temporal pattern of expression of both TFs in developing and adult mouse intestine and their expression in Muc2-expressing intestinal cells. Down-regulation of Foxa1 and Foxa2 by RNA interference in cultured intestinal cells decreased Muc2 mRNA level by half, and abolished Muc2 protein expression. Chromatin immunoprecipitation and gel shift assays showed that these two TFs directly bind to the Muc2 promoter. Co-transfection experiments indicated that both TFs activate the Muc2 promoter and that mutations of three Foxa cis-elements inhibit Muc2 transactivation. In conclusion, this work identifies Foxa1 and Foxa2 as important regulators of Muc2 expression in the intestine.
authors.affiliation: Department of Paediatrics, Division of Neonatology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Maria
authors.initials: M
authors.lastname: van der Sluis
authors.forename: Audrey
authors.initials: A
authors.lastname: Vincent
authors.forename: Janneke
authors.initials: J
authors.lastname: Bouma
authors.forename: Anita
authors.initials: A
authors.lastname: Korteland-Van Male
authors.forename: Johannes B
authors.initials: JB
authors.lastname: van Goudoever
authors.forename: Ingrid B
authors.initials: IB
authors.lastname: Renes
authors.forename: Isabelle
authors.initials: I
authors.lastname: Van Seuningen
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D024202:Electrophoretic Mobility Shift Assay; D050991:GATA4 Transcription Factor / Q000378:metabolism; D020397:Goblet Cells / Q000166:cytology / Q000378:metabolism*; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051542:Hepatocyte Nuclear Factor 3-beta / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D055262:Mucin-2; D009077:Mucins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: C496500:Foxa1 protein, mouse; C496503:Foxa2 protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; C524626:Muc2 protein, mouse; D055262:Mucin-2; D009077:Mucins; D051542:Hepatocyte Nuclear Factor 3-beta