Our main area of study is the regulation of gene expression by transcriptional repressors. We are particularly interested in how transcriptional corepressors control mammalian development and regulate cell cycle progression. We focus on two related corepressor proteins called Tgif1 and Tgif2. The major way in which Tgifs regulate gene expression is through recruitment to DNA via other DNA bound transcription factors. Once recruited to DNA Tgifs will inhibit gene expression, and their function appears to be to limit transcriptional activation in response to specific signaling pathways.

Activation of gene expression by transforming growth factor beta (TGFβ) is the best studied target of the Tgifs. The gene responses activated by TGFβ family signaling underlie many developmental and proliferative responses in mammalian cells. For example, perturbation of TGFβ signaling due to mutations in components of the signal transduction pathway contributes to numerous human cancers. In response to TGFβ signaling, Smad transcription factors accumulate in the nucleus, where they activate target gene expression. Tgifs compete with transcriptional coactivators for Smad interaction, and recruit corepressors to limit the activation of TGFβ/Smad target genes.

Our recent work has demonstrated that Tgif1 can also be recruited to DNA indirectly via interaction with the RXR nuclear receptor. RXR is a partner for many other nuclear receptors, including retinoic acid receptors, and Tgif1 represses a subset of nuclear receptor targets, including genes which are responsive to retinoic acid. We are currently examining the role of Tgif1 in other RXR-dependent nuclear receptor signaling pathways.

At present, we are continuing to analyze the mechanism by which Tgifs function, using standard biochemical approaches. We are also attempting to identify, more globally, which genes are regulated by Tgifs using expression microarray technology, and testing recruitment of Tgifs, and associated corepressors, to target genes.

To understand the physiological role of Tgifs, we have created mouse knock-outs of both Tgif and Tgif2. Complete loss of both Tgifs results in gastrulation defects and embryonic lethality, and we are trying to understand how Tgifs regulate early embryonic development. In addition, we are using conditional mutations to study Tgif function in specific tissues, and to determine which pathways Tgifs regulate.

Selected References

Melhuish TA, Chung DD, Bjerke GA, Wotton D. (2010) "Tgif1 represses apolipoprotein gene expression in liver." J Cell Biochem. Oct 111:380-90. [PubMed]

Merrill JC, Kagey MH, Melhuish TA, Powers SE, Zerlanko BJ, Wotton D. (2010) "Inhibition of CtBP1 activity by Akt-mediated phosphorylation." J Mol Biol. May 398:657-71. Epub 2010 Mar 31. [PubMed]

Merrill JC, Melhuish TA, Kagey MH, Yang SH, Sharrocks AD, Wotton D. (2010) "A role for non-covalent SUMO interaction motifs in Pc2/CBX4 E3 activity." PLoS One. Jan 5:e8794. [PubMed]

Powers SE, Taniguchi K, Yen W, Melhuish TA, Shen J, Walsh CA, Sutherland AE,Wotton D. (2010) "Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation." Development. 137:249-59. [PubMed]

Bartholin L, Melhuish TA, Powers SE, Goddard-Leon S, Treilleux I, Sutherland AE,Wotton D. (2008) "Maternal Tgif is required for vascularization of the embryonic placenta." Dev Biol. Jul 319:285-97. Epub 2008 May 2. [PubMed]

Bartholin L, Powers SE, Melhuish TA, Lasse S, Weinstein M, Wotton D. (2006) "TGIF inhibits retinoid signaling." Mol Cell Biol. 26:990-1001. [PubMed]

Kagey MH, Melhuish TA, Powers SE, Wotton D. (2005) "Multiple activities contribute to Pc2 E3 function." EMBO J. Jan 24:108-19. Epub 2004 Dec 9. [PubMed]

Hyman CA, Bartholin L, Newfeld SJ, Wotton D. (2003) "Drosophila TGIF proteins are transcriptional activators." Mol Cell Biol. 23(24):9262-74. [PubMed]

Kagey MH, Melhuish TA, Wotton D. (2003) "The polycomb protein Pc2 is a SUMO E3." Cell. Apr 113:127-37. [PubMed]