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-lot (ttNF-lot), 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-lot 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-lot, and FOG-2 are all co- expressed 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-1 _ 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-lct 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061382-05
Application #
7163404
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Carrington, Jill L
Project Start
2003-01-15
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2008-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$268,261
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
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Baffour-Awuah, Nana Yaa; Fleet, Sarah; Montgomery, Robert K et al. (2015) Functional significance of single nucleotide polymorphisms in the lactase gene in diverse US patients and evidence for a novel lactase persistence allele at -13909 in those of European ancestry. J Pediatr Gastroenterol Nutr 60:182-91
Aronson, Boaz E; Stapleton, Kelly A; Krasinski, Stephen D (2014) Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium. Am J Physiol Gastrointest Liver Physiol 306:G474-90
Aronson, B E; Rabello Aronson, S; Berkhout, R P et al. (2014) GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27. Biochim Biophys Acta 1839:1273-82
Aronson, Boaz E; Stapleton, Kelly A; Vissers, Laurens A T M et al. (2014) Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine. BMC Mol Biol 15:3
Beuling, Eva; Aronson, Boaz E; Tran, Luc M D et al. (2012) GATA6 is required for proliferation, migration, secretory cell maturation, and gene expression in the mature mouse colon. Mol Cell Biol 32:3392-402
Muncan, Vanesa; Heijmans, Jarom; Krasinski, Stephen D et al. (2011) Blimp1 regulates the transition of neonatal to adult intestinal epithelium. Nat Commun 2:452
Beuling, Eva; Baffour-Awuah, Nana Yaa A; Stapleton, Kelly A et al. (2011) GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. Gastroenterology 140:1219-1229.e1-2
Baffour-Awuah, Nana Yaa; Delemarre, Eveline; Fujiwara, Yuko et al. (2011) Characterization of expression in mice of a transgene containing 3.3 kb of the human lactase-phlorizin hydrolase (LPH) 5' flanking sequence. Dig Dis Sci 56:59-69
Beuling, Eva; Kerkhof, Ilona M; Nicksa, Grace A et al. (2010) Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine. Gut 59:888-95

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