David Wotton
Associate Professor of Biochemistry & Molecular Genetics
Member, Center for Cell Signalling
Ph.D., Imperial Cancer Research Fund, London
Transcriptional Repressors in Development and Disease

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The overall interest of our lab is to understand how signaling by the Transforming Growth Factor beta (TGF beta) pathway controls normal mammalian development, and how defects in this pathway contribute to cancer progression.

Work in the lab is currently focused on two areas. One area of interest is the regulation of prostate cancer progression by TGF beta signaling. Prostate cancer is the second leading cause of deaths due to cancer in men, and understanding how this cancer progresses to aggressive metastatic disease will be important for designing better therapies. We have created a number of mouse models in which we combined mutations in known prostate tumor suppressor genes with mutations in the TGF beta pathway. This work suggests that TGF beta signaling is a major restraint on tumor progression in prostate, and also that the activity of the pathway is induced in a subset of prostate tumors, thereby slowing their progression to invasive cancer. We are now using these mouse models, along with xenografts and in vitro cell culture models, to try to understand how TGF beta signaling limits tumor progression, the role TGF beta signaling plays in metastasis of prostate cancer, and how the TGF beta pathway becomes activated in primary prostate cancers. Additionally, we are taking genome-wide approaches to understanding how gene expression patterns and chromatin binding by key transcription factors change with tumor progression. A second major focus in the lab is the control of early mammalian development, and particularly neural tube development, by TGF beta signaling. For several years we have been studying two related transcriptional co-repressors (Tgif1 and Tgif2) that limit the transcriptional response to TGF beta signaling. In humans, mutations and deletions of Tgif1 are associated with holoprosencephaly (HPE), a severe developmental disease affecting forebrain development. In addition to trying to understand the cell and molecular basis for this disease and for the functions of Tgifs in normal forebrain development, we are also studying how TGF beta signaling, and the Tgif proteins in particular, control neural development. We have developed conditional mouse models that allow us to delete both Tgif1 and Tgif2. This results in HPE and forebrain defects in these embryos, and in patterning and cell polarity defects throughout the neural tube. We are now trying to understand the basis for the defects in neural cell polarity, determine how polarity defects contribute to HPE, and identify the primary molecular changes that drive the neural tube and forebrain defects in the absence of Tgifs. An important aspect of this is to determine how TGF beta signaling and Tgif function intersect with other important developmental pathways, including sonic hedgehog signaling. Finally, we are now beginning to use cell culture models to analyze the regulation of gene expression by Tgifs on a genome-wide scale, and more specifically, to test their role in repressing Nanog expression and regulating embryonic stem cell differentiation.

Selected References

Zerlanko BJ, Bartholin L, Melhuish TA, Wotton D. (2012) "Premature senescence and increased TGFβ signaling in the absence of Tgif1." PLoS One. 7:e35460. doi: 10.1371/journal.pone.0035460. Epub 2012 Apr 13. [PubMed]

Taniguchi K, Anderson AE, Sutherland AE, Wotton D. (2012) "Loss of Tgif function causes holoprosencephaly by disrupting the SHH signaling pathway." PLoS Genet. 8:e1002524. doi: 10.1371/journal.pgen.1002524. Epub 2012 Feb 23. [PubMed]

Bjerke GA, Hyman-Walsh C, Wotton D. (2011) "Cooperative transcriptional activation by Klf4, Meis2, and Pbx1." Mol Cell Biol. 31(18):3723-33. doi: 10.1128/MCB.01456-10. Epub 2011 Jul 11. [PubMed]

Hyman-Walsh C, Bjerke GA, Wotton D. (2010) "An autoinhibitory effect of the homothorax domain of Meis2." FEBS J. 277(12):2584-97. doi: 10.1111/j.1742-464X.2010.07668.x. [PubMed]

Hyman-Walsh C, Bjerke GA, Wotton D. (2010) "An autoinhibitory effect of the homothorax domain of Meis2." FEBS J. 277(12):2584-97. doi: 10.1111/j.1742-464X.2010.07668.x. [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. doi: 10.1016/j.jmb.2010.03.048. 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. doi: 10.1371/journal.pone.0008794. [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. doi: 10.1242/dev.040782. [PubMed]