GATA4 mediates gene repression in the mature mouse small intestine through interactions with friend of GATA (FOG) cofactors.
GATA4, a transcription factor expressed in the proximal small intestine but not in the distal ileum, maintains proximal-distal distinctions by multiple processes involving gene repression, gene activation, and cell fate determination. Friend of GATA (FOG) is an evolutionarily conserved family of cofactors whose members physically associate with GATA factors and mediate GATA-regulated repression in multiple tissues. Using a novel, inducible, intestine-specific Gata4 knock-in model in mice, in which wild-type GATA4 is specifically inactivated in the small intestine, but a GATA4 mutant that does not bind FOG cofactors (GATA4ki) continues to be expressed, we found that ileal-specific genes were significantly induced in the proximal small intestine (P<0.01); in contrast, genes restricted to proximal small intestine and cell lineage markers were unaffected, indicating that GATA4-FOG interactions contribute specifically to the repression function of GATA4 within this organ. Fog1 mRNA displayed a proximal-distal pattern that parallels that of Gata4, and FOG1 protein was co-expressed with GATA4 in intestinal epithelial cells, implicating FOG1 as the likely mediator of GATA4 function in the small intestine. Our data are the first to indicate FOG function and expression in the mammalian small intestine.
Beuling
Eva
E
School of Medicine, Erasmus University Rotterdam, Rotterdam, 3000DR, The Netherlands.
Bosse
Tjalling
T
aan de Kerk
Daniel J
DJ
Piaseckyj
Christina M
CM
Fujiwara
Yuko
Y
Katz
Samuel G
SG
Orkin
Stuart H
SH
Grand
Richard J
RJ
Krasinski
Stephen D
SD
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D007408:Intestinal Absorption / Q000235:genetics; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity / Q000235:genetics; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D015415:Biomarkers; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D009687:Nuclear Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D012333:RNA, Messenger; D027981:Symporters; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; C071908:sodium-bile acid cotransporter