Tgif1 represses apolipoprotein gene expression in liver.
TG-interacting factor (Tgif1) represses gene expression by interaction with general corepressors, and can be recruited to target genes by transforming growth factor beta (TGFβ) activated Smads, or by the retinoid X receptor (RXR). Here we show that Tgif1 interacts with the LXRα nuclear receptor and can repress transcription from a synthetic reporter activated by LXRα. In cultured cells reducing endogenous Tgif1 levels resulted in increased expression of LXRα target genes. To test the in vivo role of Tgif1, we analyzed LXRα-dependent gene expression in mice lacking Tgif1. In the livers of Tgif1 null mice, we observed significant derepression of the apolipoprotein genes, Apoa4 and Apoc2, suggesting that Tgif1 is an important in vivo regulator of apolipoprotein gene expression. In contrast, we observed relatively minimal effects on expression of other LXR target genes. This work suggests that Tgif1 can regulate nuclear receptor complexes, in addition to those containing retinoic acid receptors, but also indicates that there is some specificity to which NR target genes are repressed by Tgif1.
Melhuish
Tiffany A
TA
Department of Biochemistry and Molecular Genetics, Center for Cell Signaling, University of Virginia, Charlottesville, Virginia, USA.
Chung
David D
DD
Bjerke
Glen A
GA
Wotton
David
D
D000818:Animals; D053304:Apolipoprotein C-II / Q000032:analysis / Q000235:genetics; D001053:Apolipoproteins / Q000032:analysis / Q000235:genetics*; D001054:Apolipoproteins A / Q000032:analysis / Q000235:genetics; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology*
D053304:Apolipoprotein C-II; D001053:Apolipoproteins; D001054:Apolipoproteins A; D018398:Homeodomain Proteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C490797:Tgif1 protein, mouse; C022205:apolipoprotein A-IV