title: Transcription factors GATA4 and HNF4A control distinct aspects of intestinal homeostasis in conjunction with transcription factor CDX2.
abstract: Distinct groups of transcription factors (TFs) assemble at tissue-specific cis-regulatory sites, implying that different TF combinations may control different genes and cellular functions. Within such combinations, TFs that specify or maintain a lineage and are therefore considered master regulators may play a key role. Gene enhancers often attract these tissue-restricted TFs, as well as TFs that are expressed more broadly. However, the contributions of the individual TFs to combinatorial regulatory activity have not been examined critically in many cases in vivo. We address this question using a genetic approach in mice to inactivate the intestine-specifying and intestine-restricted factor CDX2 alone or in combination with its more broadly expressed partner factors, GATA4 and HNF4A. Compared with single mutants, each combination produced significantly greater defects and rapid lethality through distinct anomalies. Intestines lacking Gata4 and Cdx2 were deficient in crypt cell replication, whereas combined loss of Hnf4a and Cdx2 specifically impaired viability and maturation of villus enterocytes. Integrated analysis of TF binding and of transcripts affected in Hnf4a;Cdx2 compound-mutant intestines indicated that this TF pair controls genes required to construct the apical brush border and absorb nutrients, including dietary lipids. This study thus defines combinatorial TF activities, their specific requirements during tissue homeostasis, and modules of transcriptional targets in intestinal epithelial cells in vivo.
authors.affiliation: From the Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, the Graduate Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Adrianna K
authors.initials: AK
authors.lastname: San Roman
authors.affiliation: the Division of Pediatric Gastroenterology and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, Emma Children's Hospital, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Boaz E
authors.initials: BE
authors.lastname: Aronson
authors.affiliation: the Division of Pediatric Gastroenterology and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Krasinski
authors.affiliation: From the Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, and ramesh_shivdasani@dfci.harvard.edu.
authors.forename: Ramesh A
authors.initials: RA
authors.lastname: Shivdasani
authors.affiliation: From the Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, the Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854 verzi@biology.rutgers.edu.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Verzi
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation; D047369:Chromatin Immunoprecipitation; D020895:Enterocytes / Q000166:cytology; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors
keywords: CDX2 Transcription Factor; Cell Differentiation; Cell Proliferation; GATA Transcription Factor; Gene Regulation; HNF4A Transcription Factor; Intestinal Epithelium; Lipid Metabolism