Skip to main content
David Wotton

David Wotton

Professor, Biochemistry and Molecular Genetics

Primary Location
Center for Cell Signaling, Hospital West
HSC 800577, Rm #7008 (office), Rm# 7161 (lab)
Charlottesville, VA 22908
Primary Phone Number
434.243.6752
Fax Number
434.924.0226
Email
[email protected]
Website
https://research.med.virginia.edu/cell-signaling/faculty-new/?id=26107

Bio & Overview

Analysis of the role of TGIFs during development. TGIF proteins are transcriptional repressors, which regulate TGFβ signaling and have been suggested to repress retinoid regulated gene expression. Mutations in human TGIF are associated with holoprosencephaly (HPE), suggesting an important role in brain development and craniofacial morphogenesis. We have knocked out both Tgif1 and Tgif2 in mice and are analyzing defects in single and double mutant mice. We have shown that Tgif1;Tgif2 conditional double mutant mice develop HPE that is dependent on disruption of Sonic Hedgehog (Shh) signaling. We are currently analyzing the mechanisms by which loss of Tgifs and increased Nodal signaling affect the Shh pathway, cause HPE and regulate other early developmental processes. Molecular analysis of transcriptional repression by TGIFs. We are analyzing the role that Tgifs play in regulating TGFβ activated gene expression and identifying target genes using transcriptome profiling by RNA-seq, from both embryos and cultured cells. In addition, we have begun to examine transcriptional repression by Tgifs via pathways other than TGFβ signaling. We have shown that Tgif1 represses gene expression via certain nuclear receptors, and have also identified a class of neural zinc finger transcription factors with which Tgif1 interacts. We are now actively trying to understand the importance of this interaction for neural development and differentiation. One interesting possibility that we are testing is that this link between Tgifs and neural zinc finger factors plays a role in the development of glioblastoma. Analysis of the role of TGFβ signaling during prostate cancer progression. Prostate cancer is the second leading cause of deaths due to cancer in North American men. We are testing how mutations in genes that are commonly found to be mutated in human prostate cancer cooperate to drive local prostate tumors to high grade invasive cancer. We have developed a novel prostate cancer mouse model, based on mutations in the Pten and Tgfbr2 tumor suppressor genes. We will determine how mutation of the Tgfbr2 gene allows primary tumors to become invasive and metastatic, and will use this model to test the efficacy of common therapeutic approaches to human prostate cancer. Additionally, we are exploring the pathways that are regulated by TGFβ in prostate that contribute to prostate cancer progression when the pathway is disrupted. Finally we are trying to generate better mouse models of prostate cancer that will better allow us to study metastasis.

Academic Information

Department
Biochemistry and Molecular Genetics
Academic Title
Professor

Primary Education

  • BS, Genetics, University of York, England, 1985
  • PhD, Genetics, Imperial Cancer Research Fund, London, 1994

Other Appointments

  • Professor, Cell Biology
  • Associate Professor, BMBG
  • Associate Professor, MCDB
  • Associate Professor, MOMD

Other Affiliations

  • Associate Professor, Arts & Sciences
  • Member, Molecular Genetics and Epigenetics Program
  • Associate Professor, BIMS

Research Interests

Regulation of Gene Expression, Development and Tumor Progression by TGF beta Signaling

Research Disciplines

  • Biochemistry
  • Cancer Biology
  • Cell and Developmental Biology
  • Development, Stem Cells & Regeneration
  • Epigenetics
  • Genetics
  • Metabolism
  • Molecular Biology

Research Opportunities

  • Biochemistry
  • Cancer Biology
  • Cell Biology
  • Cellular and Molecular Metabolism
  • Development, Stem Cells & Regeneration
  • Epigenetics
  • Genetics
  • Molecular Biology

PhD Programs

  • Biochemistry & Molecular Genetics
  • Cell Biology

Selected Publications

2023

Yang, C., Wierbilowicz, K., Dworak, N. M., Bae, S. Y., Tengse, S. B., Abianeh, N., . . . Paschal, B. M. (2023). Induction of PARP7 Creates a Vulnerability for Growth Inhibition by RBN2397 in Prostate Cancer Cells. CANCER RESEARCH COMMUNICATIONS, 3(4), 592-606. doi:10.1158/2767-9764.CRC-23-0086

2021

Yang, C. -S., Jividen, K., Kamata, T., Dworak, N., Oostdyk, L., Remlein, B., . . . Paschal, B. M. (2021). Androgen signaling uses a writer and a reader of ADP-ribosylation to regulate protein complex assembly. NATURE COMMUNICATIONS, 12(1). doi:10.1038/s41467-021-23055-6

Kamata, T., Yang, C. -S., Melhuish, T. A., Frierson Jr., H. F., Wotton, D., & Paschal, B. M. (2021). Post-Transcriptional Regulation of PARP7 Protein Stability Is Controlled by Androgen Signaling. CELLS, 10(2). doi:10.3390/cells10020363

2020

Saha, S., Kiran, M., Kuscu, C., Chatrath, A., Wotton, D., Mayo, M. W., & Dutta, A. (2020). Long Noncoding RNA DRAIC Inhibits Prostate Cancer Progression by Interacting with IKK to Inhibit NF-κB Activation. CANCER RESEARCH, 80(5), 950-963. doi:10.1158/0008-5472.CAN-19-3460

2019

Shah, A., Melhuish, T. A., Fox, T. E., Frierson, H. F. J., & Wotton, D. (2019). TGIF transcription factors repress acetyl CoA metabolic gene expression and promote intestinal tumor growth. GENES & DEVELOPMENT, 33(7-8), 388-402. doi:10.1101/gad.320127.118

2018

Melhuish, T. A., Kowalczyk, I., Manukyan, A., Zhang, Y., Shah, A., Abounader, R., & Wotton, D. (2018). Myt1 and Myth1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, 1861(11), 983-995. doi:10.1016/j.bbagrm.2018.10.005

Parini, P., Melhuish, T. A., Wotton, D., Larsson, L., Ahmed, O., Eriksson, M., & Pramfalk, C. (2018). Overexpression of transforming growth factor β induced factor homeobox 1 represses NPC1L1 and lowers markers of intestinal cholesterol absorption. ATHEROSCLEROSIS, 275, 246-255. doi:10.1016/j.atherosclerosis.2018.06.867

Wotton, D., & Taniguchi, K. (2018). Functions of TGIF homeodomain proteins and their roles in normal brain development and holoprosencephaly. AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS, 178(2), 128-139. doi:10.1002/ajmg.c.31612

Hao, Y., Bjerke, G. A., Pietrzak, K., Melhuish, T. A., Han, Y., Turner, S. D., . . . Wotton, D. (2018). TGFβ signaling limits lineage plasticity in prostate cancer. PLOS GENETICS, 14(5). doi:10.1371/journal.pgen.1007409

Carlton, A. L., Illendula, A., Gao, Y., Llaneza, D. C., Boulton, A., Shah, A., . . . Bushweller, J. H. (2018). Small molecule inhibition of the CBFβ/RUNX interaction decreases ovarian cancer growth and migration through alterations in genes related to epithelial-to-mesenchymal transition. GYNECOLOGIC ONCOLOGY, 149(2), 350-360. doi:10.1016/j.ygyno.2018.03.005

Manukyan, A., Kowalczyk, I., Melhuish, T. A., Lemiesz, A., & Wotton, D. (2018). Analysis of transcriptional activity by the Myt1 and Myt1l transcription factors. JOURNAL OF CELLULAR BIOCHEMISTRY, 119(6), 4644-4655. doi:10.1002/jcb.26636

2017

Yang, C. -S., Melhuish, T. A., Spencer, A., Ni, L., Hao, Y., Jividen, K., . . . Paschal, B. M. (2017). The protein kinase C super-family member PKN is regulated by mTOR and influences differentiation during prostate cancer progression. PROSTATE, 77(15), 1452-1467. doi:10.1002/pros.23400

Anderson, A. E., Taniguchi, K., Hao, Y., Melhuish, T. A., Shah, A., Turner, S. D., . . . Wotton, D. (2017). Tgif1 and Tgif2 Repress Expression of the RabGAP Evi5l. MOLECULAR AND CELLULAR BIOLOGY, 37(5). doi:10.1128/MCB.00527-16

Wotton, D., Pemberton, L. F., & Merrill-Schools, J. (2017). SUMO and Chromatin Remodeling. SUMO REGULATION OF CELLULAR PROCESSES, 2ND EDITION, 963, 35-50. doi:10.1007/978-3-319-50044-7_3

2016

Taniguchi, K., Anderson, A. E., Melhuish, T. A., Carlton, A. L., Manukyan, A., Sutherland, A. E., & Wotton, D. (2017). Genetic and Molecular Analyses indicate independent effects of TGIFs on Nodal and Gli3 in neural tube patterning. EUROPEAN JOURNAL OF HUMAN GENETICS, 25(2), 208-215. doi:10.1038/ejhg.2016.164

Melhuish, T. A., Taniguchi, K., & Wotton, D. (2016). Tgif1 and Tgif2 Regulate Axial Patterning in Mouse. PLOS ONE, 11(5). doi:10.1371/journal.pone.0155837

2014

Wotton, D. (2014). A CREB1-TGFβ2 Self-Sustaining Loop in Glioblastoma. CANCER DISCOVERY, 4(10), 1123-1125. doi:10.1158/2159-8290.CD-14-0861

Pramfalk, C., Melhuish, T. A., Wotton, D., Jiang, Z. -Y., Eriksson, M., & Parini, P. (2014). TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2. JOURNAL OF LIPID RESEARCH, 55(4), 709-717. doi:10.1194/jlr.M045922

Bjerke, G. A., Pietrzak, K., Melhuish, T. A., Frierson, H. F. J., Paschal, B. M., & Wotton, D. (2014). Prostate Cancer Induced by Loss of Apc Is Restrained by TGFβ Signaling. PLOS ONE, 9(3). doi:10.1371/journal.pone.0092800

2013

Yan, L., Womack, B., Wotton, D., Guo, Y., Shyr, Y., Dave, U., . . . Hamid, R. (2013). Tgif1 Regulates Quiescence and Self-Renewal of Hematopoietic Stem Cells. MOLECULAR AND CELLULAR BIOLOGY, 33(24), 4824-4833. doi:10.1128/MCB.01076-13

Bjerke, G. A., Yang, C. -S., Frierson, H. F., Paschal, B. M., & Wotton, D. (2014). Activation of Akt signaling in prostate induces a TGFβ-mediated restraint on cancer progression and metastasis. ONCOGENE, 33(28), 3660-3667. doi:10.1038/onc.2013.342

2012

Wotton, D. (2012). TGF-β Drives DNA Demethylation. MOLECULAR CELL, 46(5), 556-557. doi:10.1016/j.molcel.2012.05.031

Taniguchi, K., Anderson, A. E., Sutherland, A. E., & Wotton, D. (2012). Loss of Tgif Function Causes Holoprosencephaly by Disrupting the Shh Signaling Pathway. PLOS GENETICS, 8(2). doi:10.1371/journal.pgen.1002524

Zerlanko, B. J., Bartholin, L., Melhuish, T. A., & Wotton, D. (2012). Premature Senescence and Increased TGFβ Signaling in the Absence of Tgif1. PLOS ONE, 7(4). doi:10.1371/journal.pone.0035460

2011

Bjerke, G. A., Hyman-Walsh, C., & Wotton, D. (2011). Cooperative Transcriptional Activation by Klf4, Meis2, and Pbx1. MOLECULAR AND CELLULAR BIOLOGY, 31(18), 3723-3733. doi:10.1128/MCB.01456-10

2010

Wotton, D. (2010). Regulation of transcription of the human CD2 and T cell receptor β chain genes..

Vincent, D. F., Kaniewski, B., Powers, S. E., Havenar-Daughton, C., Marie, J. C., Wotton, D., & Bartholin, L. (2010). A Rapid Strategy to Detect the Recombined Allele in LSL-TβRICA Transgenic Mice. GENESIS, 48(9), 559-562. doi:10.1002/dvg.20653

Quijano, J. C., Stinchfield, M. J., Zerlanko, B., Gibbens, Y. Y., Takaesu, N. T., Hyman-Walsh, C., . . . Newfeld, S. J. (2010). The Sno Oncogene Antagonizes Wingless Signaling during Wing Development in Drosophila. PLOS ONE, 5(7). doi:10.1371/journal.pone.0011619

Hyman-Walsh, C., Bjerke, G. A., & Wotton, D. (2010). An autoinhibitory effect of the homothorax domain of Meis2. FEBS JOURNAL, 277(12), 2584-2597. doi:10.1111/j.1742-4658.2010.07668.x

Melhuish, T. A., Chung, D. D., Bjerke, G. A., & Wotton, D. (2010). Tgif1 Represses Apolipoprotein Gene Expression in Liver. JOURNAL OF CELLULAR BIOCHEMISTRY, 111(2), 380-390. doi:10.1002/jcb.22713

Merrill, J. C., Kagey, M. H., Melhuish, T. A., Powers, S. E., Zerlanko, B. J., & Wotton, D. (2010). Inhibition of CtBP1 Activity by Akt-mediated Phosphorylation. JOURNAL OF MOLECULAR BIOLOGY, 398(5), 657-671. doi:10.1016/j.jmb.2010.03.048

Merrill, J. C., Melhuish, T. A., Kagey, M. H., Yang, S. -H., Sharrocks, A. D., & Wotton, D. (2010). A Role for Non-Covalent SUMO Interaction Motifs in Pc2/CBX4 E3 Activity. PLOS ONE, 5(1). doi:10.1371/journal.pone.0008794

Powers, S. E., Taniguchi, K., Yen, W., Melhuish, T. A., Shen, J., Walsh, C. A., . . . Wotton, D. (2010). Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation. DEVELOPMENT, 137(2), 249-259. doi:10.1242/dev.040782