Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Cell Mol Gastroenterol Hepatol
2017 May 24;33:422-446. doi: 10.1016/j.jcmgh.2016.12.009.
Show Gene links
Show Anatomy links
GATA4 Is Sufficient to Establish Jejunal Versus Ileal Identity in the Small Intestine.
Thompson CA
,
Wojta K
,
Pulakanti K
,
Rao S
,
Dawson P
,
Battle MA
.
???displayArticle.abstract???
BACKGROUND & amp; AIMS: Patterning of the small intestinal epithelium along its cephalocaudal axis establishes three functionally distinct regions: duodenum, jejunum, and ileum. Efficient nutrient assimilation and growth depend on the proper spatial patterning of specialized digestive and absorptive functions performed by duodenal, jejunal, and ileal enterocytes. When enterocyte function is disrupted by disease or injury, intestinal failure can occur. One approach to alleviate intestinal failure would be to restore lost enterocyte functions. The molecular mechanisms determining regionally defined enterocyte functions, however, are poorly delineated. We previously showed that GATA binding protein 4 (GATA4) is essential to define jejunal enterocytes. The goal of this study was to test the hypothesis that GATA4 is sufficient to confer jejunal identity within the intestinal epithelium.
METHODS: To test this hypothesis, we generated a novel Gata4 conditional knock-in mouse line and expressed GATA4 in the ileum, where it is absent.
RESULTS: We found that GATA4-expressing ileum lost ileal identity. The global gene expression profile of GATA4-expressing ileal epithelium aligned more closely with jejunum and duodenum rather than ileum. Focusing on jejunal vs ileal identity, we defined sets of jejunal and ileal genes likely to be regulated directly by GATA4 to suppress ileal identity and promote jejunal identity. Furthermore, our study implicates GATA4 as a transcriptional repressor of fibroblast growth factor 15 (Fgf15), which encodes an enterokine that has been implicated in an increasing number of human diseases.
CONCLUSIONS: Overall, this study refines our understanding of an important GATA4-dependent molecular mechanism to pattern the intestinal epithelium along its cephalocaudal axis by elaborating on GATA4's function as a crucial dominant molecular determinant of jejunal enterocyte identity. Microarray data from this study have been deposited into NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) and are accessible through GEO series accession number GSE75870.
Aronson,
GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.
2014, Pubmed
Aronson,
GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.
2014,
Pubmed
Battle,
GATA4 is essential for jejunal function in mice.
2008,
Pubmed
Beuling,
GATA4 mediates gene repression in the mature mouse small intestine through interactions with friend of GATA (FOG) cofactors.
2008,
Pubmed
Bondow,
E-cadherin is required for intestinal morphogenesis in the mouse.
2012,
Pubmed
Bossard,
Repressive and restrictive mesodermal interactions with gut endoderm: possible relation to Meckel's Diverticulum.
2000,
Pubmed
Bosse,
Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestine.
2006,
Pubmed
Davis,
Deletion of the ileal basolateral bile acid transporter identifies the cellular sentinels that regulate the bile acid pool.
2008,
Pubmed
Dawson,
The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter.
2005,
Pubmed
Driegen,
A generic tool for biotinylation of tagged proteins in transgenic mice.
2005,
Pubmed
Duncan,
Murine gastrulation requires HNF-4 regulated gene expression in the visceral endoderm: tetraploid rescue of Hnf-4(-/-) embryos.
1997,
Pubmed
Fang,
Spatio-temporal patterns of intestine-specific transcription factor expression during postnatal mouse gut development.
2006,
Pubmed
Ferrebee,
Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids.
2015,
Pubmed
Friedrich,
Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice.
1991,
Pubmed
Gao,
Distinct functions are implicated for the GATA-4, -5, and -6 transcription factors in the regulation of intestine epithelial cell differentiation.
1998,
Pubmed
Grober,
Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer.
1999,
Pubmed
Guo,
Retinoblastoma protein (pRb), but not p107 or p130, is required for maintenance of enterocyte quiescence and differentiation in small intestine.
2009,
Pubmed
Gutierrez,
Neonatal short bowel syndrome.
2011,
Pubmed
Hagenbuch,
The sodium bile salt cotransport family SLC10.
2004,
Pubmed
He,
PRC2 directly methylates GATA4 and represses its transcriptional activity.
2012,
Pubmed
He,
Genome-wide location analysis by pull down of in vivo biotinylated transcription factors.
2010,
Pubmed
Inagaki,
Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.
2005,
Pubmed
Jahn,
Mechanisms of enterohepatic fibroblast growth factor 15/19 signaling in health and disease.
2015,
Pubmed
Ji,
An integrated software system for analyzing ChIP-chip and ChIP-seq data.
2008,
Pubmed
Jung,
FXR agonists and FGF15 reduce fecal bile acid excretion in a mouse model of bile acid malabsorption.
2007,
Pubmed
Keely,
The Farnesoid X Receptor: Good for BAD.
2016,
Pubmed
Kim,
Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine.
2007,
Pubmed
Kliewer,
Bile Acids as Hormones: The FXR-FGF15/19 Pathway.
2015,
Pubmed
Kohlnhofer,
GATA4 regulates epithelial cell proliferation to control intestinal growth and development in mice.
2016,
Pubmed
Landrier,
The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes.
2006,
Pubmed
Landrier,
Regulation of the ileal bile acid-binding protein gene: an approach to determine its physiological function(s).
2002,
Pubmed
Lee,
FXR, a multipurpose nuclear receptor.
2006,
Pubmed
Madison,
Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine.
2002,
Pubmed
Middendorp,
Adult stem cells in the small intestine are intrinsically programmed with their location-specific function.
2014,
Pubmed
Nagy,
Derivation of completely cell culture-derived mice from early-passage embryonic stem cells.
1993,
Pubmed
Owen,
Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21.
2015,
Pubmed
Rojas,
GATA4 is a direct transcriptional activator of cyclin D2 and Cdk4 and is required for cardiomyocyte proliferation in anterior heart field-derived myocardium.
2008,
Pubmed
Sanderson,
Dietary regulation of genes expressed in the developing intestinal epithelium.
1998,
Pubmed
Song,
Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.
2009,
Pubmed
Soriano,
Generalized lacZ expression with the ROSA26 Cre reporter strain.
1999,
Pubmed
Spence,
Vertebrate intestinal endoderm development.
2011,
Pubmed
Srinivas,
Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.
2001,
Pubmed
Subramanian,
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles.
2005,
Pubmed
van den Brink,
Hedgehog signaling in development and homeostasis of the gastrointestinal tract.
2007,
Pubmed
van Wering,
Complex regulation of the lactase-phlorizin hydrolase promoter by GATA-4.
2004,
Pubmed
Wales,
Neonatal short bowel syndrome: population-based estimates of incidence and mortality rates.
2004,
Pubmed
Walker,
Characterization of the developing small intestine in the absence of either GATA4 or GATA6.
2014,
Pubmed
Walker,
GATA4 and GATA6 regulate intestinal epithelial cytodifferentiation during development.
2014,
Pubmed
Watt,
GATA4 is essential for formation of the proepicardium and regulates cardiogenesis.
2004,
Pubmed
Wood,
Non-injection methods for the production of embryonic stem cell-embryo chimaeras.
1993,
Pubmed
Zambrowicz,
Disruption of overlapping transcripts in the ROSA beta geo 26 gene trap strain leads to widespread expression of beta-galactosidase in mouse embryos and hematopoietic cells.
1997,
Pubmed
Zhang,
Model-based analysis of ChIP-Seq (MACS).
2008,
Pubmed
Zheng,
Function of GATA factors in the adult mouse liver.
2013,
Pubmed
