Regulation of Intestinal Gene Expression

Summary

Principal Investigator: STEPHEN KRASINSKI
Affiliation: Harvard University
Country: USA
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

Top Publications

  1. pmc GATA4 mediates gene repression in the mature mouse small intestine through interactions with friend of GATA (FOG) cofactors
    Eva Beuling
    School of Medicine, Erasmus University Rotterdam, Rotterdam, 3000DR, The Netherlands
    Dev Biol 322:179-89. 2008
  2. pmc Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine
    Boaz 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
  3. pmc Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium
    Boaz 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
  4. pmc GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colon
    Eva 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
  5. pmc GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice
    Eva Beuling
    Division of Gastroenterology and Nutrition, Department of Medicine, Children s Hospital Boston, Boston, Massachusetts, USA
    Gastroenterology 140:1219-1229.e1-2. 2011
  6. pmc Characterization of expression in mice of a transgene containing 3.3 kb of the human lactase-phlorizin hydrolase (LPH) 5' flanking sequence
    Nana 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
  7. pmc Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine
    Eva Beuling
    GI Cell Biology, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
    Gut 59:888-95. 2010
  8. ncbi 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
  9. ncbi Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development
    Tjalling Bosse
    School of Medicine, University of Amsterdam, Amsterdam, The Netherlands
    Am J Physiol Gastrointest Liver Physiol 292:G1302-14. 2007
  10. pmc Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestine
    Tjalling Bosse
    GI Cell Biology, EN 720, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
    Mol Cell Biol 26:9060-70. 2006

Detail Information

Publications11

  1. pmc GATA4 mediates gene repression in the mature mouse small intestine through interactions with friend of GATA (FOG) cofactors
    Eva 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...
  2. pmc Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine
    Boaz 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
    ....
  3. pmc Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium
    Boaz 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. ..
  4. pmc GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colon
    Eva 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...
  5. pmc GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice
    Eva 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...
  6. pmc Characterization of expression in mice of a transgene containing 3.3 kb of the human lactase-phlorizin hydrolase (LPH) 5' flanking sequence
    Nana 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...
  7. pmc Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine
    Eva Beuling
    GI Cell Biology, Children s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA
    Gut 59:888-95. 2010
    ....
  8. ncbi 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...
  9. ncbi Gata4 and Hnf1alpha are partially required for the expression of specific intestinal genes during development
    Tjalling 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...
  10. pmc Gata4 is essential for the maintenance of jejunal-ileal identities in the adult mouse small intestine
    Tjalling 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...
  11. ncbi Hepatocyte nuclear factor-1alpha is required for expression but dispensable for histone acetylation of the lactase-phlorizin hydrolase gene in vivo
    Tjalling 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-..