University of Virginia Health System

Our lab is interested in the role of transcriptional repressors in the regulation of TGF-b signaling and development. A major focus is the homeodomain protein TGIF, which recruits general corepressors to specific target genes. The gene responses activated by TGF-b family signaling underlie many developmental and proliferative events. Mutations in components of the TGF-b pathway, resulting in a loss of signaling can contribute to human cancer. Following TGF-b receptor-mediated phosphorylation, an activated Smad complex moves to the nucleus and activates gene expression. Transcriptional regulation by Smads is dependent on interactions with transcriptional coactivators and corepressors, including TGIF. Interaction of Smad proteins with TGIF precludes interaction with coactivators resulting in repression of transcription. The level of TGIF within the nucleus can thereby regulate the transcriptional outcome of a TGF-b response. Changes in TGIF levels are likely to alter the anti-proliferative effects of TGF-b signaling, suggesting that increased TGIF expression may contribute to tumorigenesis. In humans, heterozygous mutations in TGIF result in holoprosencephaly, a prevalent genetic disorder affecting craniofacial development. Thus, relatively small changes in TGIF levels can result in dramatic developmental defects. We have created mice with a targeted mutation in TGIF and are currently analyzing the developmental effects of TGIF mutation. We have shown that TGIF can repress TGF-b-activated gene expression as well as expression of other TGF-b-independent responses. We are now trying to identify the gene responses regulated by TGIF, particularly those which may play a role in brain development. In addition we are attempting to understand how TGIF targets a corepressor complex to DNA independent of the TGF-b/Smad pathway. This is likely to involve both direct DNA binding by TGIF and interaction with other, as yet unidentified, DNA binding proteins. TGIF represses transcription by recruiting general transcriptional corepressors, including histone deacetylases (HDAC) and polycomb group proteins. A current focus of the lab is to determine the importance of these different corepressor complexes in the regulation of transcription by TGIF. One possibility is that HDAC complexes play a role in repressing TGF-b-activated transcription, whereas the recruitment of polycomb proteins by TGIF is more important for stable transcriptional repression during development.

• NIH Style Biographical Sketch (UVA Intranet log-in required)