Genomes and Genes
Regulation of Intestinal Gene Expression
Principal Investigator: STEPHEN KRASINSKI
Affiliation: Harvard University
Abstract: Intestine-specific gene expression is determined by unique interactions among tissue-restricted transcriptional modulators. In this application, the PI reveals novel physical and functional interactions between members of the zinc finger subfamily, GATA-4, -5, and -6, and the tissue-restricted homeodomain transcription factor, hepatocyte nuclear factor-1alpha (HNF-1alpha), that result in synergistic activation of the promoter of the intestine specific lactase-phlorizin hydrolase (LPH) gene. This critical finding supports a paradigm whereby the overlapping expression of members of the GATA-4, -5, and -6 subfamily and HNF-1alpha regulates intestine specific gene expression in vivo. Intestine-specific gene expression may be further regulated by individual GATA factors, which reveal unique, independent functions not previously known, and by friend of GATA-2 (FOG-2), a member of a recently described multi-zinc finger family of cofactors whose expression and function in the intestine have not yet been determined. GATA factors, HNF-1alpha, and FOG-2 are all coexpressed in the intestinal epithelium indicating that interactions among these proteins is likely to occur in vivo. Based on these preliminary data, it is hypothesized that independent and overlapping expression among GATA factors, HNF-1alpha and FOG-2 are required for the tissue- and cell-type-specific expression of the LPH gene along complex crypt-villus, proximal-distal, and developmental gradients. The specific aims of the proposed studies are (I) to define the mechanism that establishes independent functions for individual GATA factors in the activation of the LPH promoter, (II) to delineate the mechanisms by which GATA-4, -5, -6 and HNF-1alpha regulate LPH gene expression in vivo, and (III) to define the significance of FOG-2 as a repressor of GATA-activated LPH gene transcription. These studies will provide a fundamental understanding of the role that evolutionarily conserved zinc finger and homeodomain proteins play in the regulation of intestine specific gene expression. Characterizing specific interactions among GATA, HNF-1, and FOG proteins will also elucidate some of the mechanisms governing the complex processes of cell-specific gene expression, cellular differentiation, and intestinal development.
Funding Period: 2003-01-15 - 2007-12-31
more information: NIH RePORT
- GATA4 mediates gene repression in the mature mouse small intestine through interactions with friend of GATA (FOG) cofactorsEva Beuling
School of Medicine, Erasmus University Rotterdam, Rotterdam, 3000DR, The Netherlands
Dev Biol 322:179-89. 2008..Our data are the first to indicate FOG function and expression in the mammalian small intestine...
- Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestineBoaz E Aronson
Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, and Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
BMC Mol Biol 15:3. 2014....
- Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epitheliumBoaz E Aronson
Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, and Harvard Medical School, Boston, Massachusetts
Am J Physiol Gastrointest Liver Physiol 306:G474-90. 2014..We offer perspective on the application of epigenetics approaches to define the mechanisms underlying context-specific GATA gene regulation during intestinal development. ..
- GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colonEva Beuling
Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, and Harvard Medical School, Boston, Massachusetts, USA
Mol Cell Biol 32:3392-402. 2012..These data demonstrate that GATA6 is necessary for proliferation, migration, lineage maturation, and gene expression in the mature colonic epithelium...
- GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature miceEva Beuling
Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, Boston, Massachusetts, USA
Gastroenterology 140:1219-1229.e1-2. 2011..GATA6 is co-expressed with GATA4 but also is expressed in the ileum; its function in the mature small intestine is unknown...
- Characterization of expression in mice of a transgene containing 3.3 kb of the human lactase-phlorizin hydrolase (LPH) 5' flanking sequenceNana Yaa Baffour-Awuah
Gastrointestinal Cell, Molecular Biology Laboratory, Division of Gastroenterology and Nutrition, Children s Hospital Boston, and Department of Pediatrics, Harvard Medical School, Enders 609 2, 300 Longwood Avenue, Boston, MA 02115, USA
Dig Dis Sci 56:59-69. 2011..To gain insight into human LCT expression, transgenic mouse lines were generated from 3.3 kb of human LPH 5' flanking sequence from a lactase persistent individual fused to a human growth hormone (hGH) reporter bounded by an insulator...
- Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestineEva Beuling
GI Cell Biology, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
Gut 59:888-95. 2010....
- Lactose and lactase--who is lactose intolerant and why?Robert K Montgomery
Division of Genetics, Department of Medicine, Program in Genomics, Children s Hospital, Boston, MA 02115, USA
J Pediatr Gastroenterol Nutr 45:S131-7. 2007..Any hypothesis for the control of lactase expression must reconcile the presence of high levels of activity in early life in all humans and the characteristic loss of activity found subsequently in many but not all people...
- Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during developmentTjalling Bosse
School of Medicine, University of Amsterdam, Amsterdam, The Netherlands
Am J Physiol Gastrointest Liver Physiol 292:G1302-14. 2007..Together, these data demonstrate that specific intestinal genes have differential requirements for Gata4 and Hnf1alpha that are dependent on the developmental time frame in which they are expressed...
- Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestineTjalling Bosse
GI Cell Biology, EN 720, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
Mol Cell Biol 26:9060-70. 2006..05). Gata4 is thus an important positional signal required for the maintenance of jejunal-ileal identities in the adult mouse small intestine...
- Hepatocyte nuclear factor-1alpha is required for expression but dispensable for histone acetylation of the lactase-phlorizin hydrolase gene in vivoTjalling Bosse
Department of Medicine, University of Amsterdam, Amsterdam, The Netherlands
Am J Physiol Gastrointest Liver Physiol 290:G1016-24. 2006..To define the importance and underlying mechanism of HNF-1alpha for the regulation of intestinal gene expression in vivo, we analyzed the expression of the intestinal differentiation markers and putative HNF-..