Stefan Roberts

My research program is focused on understanding the molecular mechanisms by which transcriptional regulators control gene expression in normal cells and in cancer.

Wilms’ tumor 1 protein: a model of activator-repressor switching

The Wilms tumor 1 protein (WT1) was first identified in pediatric nephroblastoma. WT1 is a developmental transcriptional regulator that plays a central role in the formation of multiple organs and tissues during development. WT1 can act as either an activator or a repressor of transcription, depending on the cellular context. This dichotomy is essential for WT1's roles in development and disease. We study WT1 as a model of transcriptional activator-repressor switching. We have identified several WT1 cofactors that control this dichotomous function, including the novel cofactor BASP1. BASP1 binds directly to WT1 and converts it from an activator to a repressor. Since our initial discovery of BASP1 as a WT1 cofactor, BASP1 has been found to regulate the activity of several other transcription factors, such as c-myc, YY1, and estrogen receptor α (ERα).

A critical function for nuclear lipids in transcription control

BASP1 is a lipidated protein that is modified by N-terminal myristoylation. This modification is critical for BASP1's transcription function. Lipids have been known to be present in the nucleus for several decades, but their roles in nuclear processes are poorly understood. We have found that BASP1 uses its N-terminal myristoyl motif to directly interact with lipids in the cell nucleus. These interactions are required for BASP1's transcriptional repressor function. We hypothesize that lipidated transcription factors use nuclear lipids to coordinate protein-protein interactions within the transcriptional machinery and direct chromatin modification to regulate gene expression. We are currently working to identify and characterize these events.

BASP1: A driver of the differentiated state

BASP1 is a tumor suppressor that plays a critical role in driving the differentiated state through several DNA-bound transcription factors. We have found that BASP1 cooperates with WT1 to promote differentiation to neuronal cells in vitro. In collaboration with Kathryn Medler's lab, we studied WT1 and BASP1 in mouse models and found that WT1 is important for taste bud development. Using a conditional BASP1 mouse, we found that BASP1 plays a major role in taste bud homeostasis by blocking WT1 function at critical genes from several signaling pathways. The mechanisms by which BASP1 regulates transcription to maintain the differentiated state of neuronal cells are currently under investigation.

Anuj, A., Reuven, N., Roberts, S.G.E. and Elson, A. (2023). BASP1 down-regulates RANKL-induced osteoclastogenesis. Experimental Cell Research. https://doi.org/10.1016/j.yexcr.2023.113758

Moorhouse, A.J., Loats, A.E., Medler, K.F. and Roberts, S.G.E. (2022). The BASP1 transcriptional corepressor modifies chromatin through lipid-dependent and lipid-independent mechanisms. iScience 25,104796.

Wagstaff, M., Tsaponina, O., Caalim, G., Greenfield, H., Milton-Harris, L., Mancini, E., Blair A., Tonks, A., Darley, R.L., Roberts, S.G. and Morgan, R.G. (2022). Crosstalk between b-catenin and WT1 signalling in acute myeloid leukemia. Haematologica 108, 283-289.

Loats, A.E., Carrera, S., Fleming, A.F., Roberts, A.R.E., Sherrard, A., Toska, E., Moorhouse, A.J., Medler, K.F. and Roberts, S.G.E. (2021). Cholesterol is required for transcriptional repression by BASP1. Proceedings of the National Academy of Sciences USA 118, e2101671118.

Belali, T., Wodi, C., Cheung, M.K., Craig, T.J., Wheway, G., Wagner, N., Wagner, K., Roberts, S., Porazinski, S. and Ladomery, M. (2020). WT1 activates transcription of the splice factor kinase SRPK1 gene in PC3 and K562 cancer cells in the absence of corepressor BASP1. Biochim Biophys Acta Gene Regul Mech 1863,194642.

Ahart, Z.C., Martin, L.E., Kemp, B.R., Dutta Banik, D., Roberts, S.G.E., Torregrossa A., Medler, K.F. (2019). Differential effects of diet and weight on taste responses in diet-induced obese mice. Obesity 28, 284-292.

Gao, Y., Dutta Banik, D., Muna, M.M., Roberts, S.G.E. and Medler K.F. (2019). The WT1-BASP1 complex is required to maintain the differentiated state of taste receptor cells. Life Science Alliance 2, e201800287.

Perovic, V., Sumonja, N., Marsh, L.A., Radovanovic, S., Vukicevic, M., Roberts. S.G.E. and Veljkovic, N. (2018). IDPpi: Protein-Protein Interaction Analyses of Human Intrinsically Disordered Proteins. Scientific Reports 8, 10563.

Marsh, L.A., Carrera, S., Shandilya, J., Heesom, K.J., Davidson, A.D., Medler, K.F. and Roberts, S.G.E. (2017). BASP1 Interacts with Estrogen Receptor α and Modifies the Tamoxifen Response. Cell Death and Disease 8: e2771