Postdoc opportunity - new position
Molecular mechanisms of signal-regulated MRTF activation
A postdoctoral position is immediately available for a bright, creative and hardworking postdoc with experience in gene regulation, signalling and biochemistry who is interested in studying how transcriptional the MRTF transcriptional coactivators is controlled by their interaction with G-actin.
The Signalling and Transcription group focusses on the SRF transcription factor network, a major nuclear target of Rho and Ras, two important signalling pathways involved in oncogenic transformation, invasion and metastasis. Our main interest is in the biology of SRF and its two cofactor families, the TCFs and the MRTFs, and the molecular mechanisms underlying their control by Ras-ERK and Rho-actin signalling (Olson and Nordheim, 2010; Posern and Treisman, 2006). We use a multidisciplinary approach, involving biochemistry, structural biology, cell biology and genomics, applied to both tissue culture and mouse cancer and immune models.
We have defined the direct genomic targets for SRF, and shown that Rho-actin signalling to the MRTFs is a major contributor to the fibroblast growth factor response (Esnault et al., 2014). We characterised the kinetics of ERK-induced TCF phosphorylation (Mylona et al., 2016). We evaluated the contribution of the TCFs to the transcriptional and chromatin response to ERK activation, showing that their activation is required for histone modifications at the TSS (Esnault et al., 2017). We also showed that the TCFs compete with the MRTFs for access to SRF, and that this determines the cell contractile response (Gualdrini et al., 2016). Finally we have examined the relationship between MRTF/SRF signalling and the YAP/TEAD pathway, showing that the two pathways are mutually dependent (Foster et al., 2017).
We are especially interested in the molecular mechanisms controlling MRTF activation, particularly the role played by G-actin, the relationship between MRTF phosphorylation and transcriptional activation, and how MRTF/SRF regulation controls the cellular response to growth factor and mechanical stimuli. Control of MRTF subcellular localisation is a major mechanism by which MRTF activity is regulated by G-actin (Miralles et al., 2003).
Our previous studies have shown that nuclear G-actin suppresses MRTF target gene transcription (Vartiainen et al., 2007). Our recent data show that this involves control both of MRTF-SRF interaction and DNA binding, and RNA polymerase II recruitment and initiation: we are using biochemical and genomic approaches to elucidate the molecular mechanisms involved. A second area of interest concerns the relationship between signalling to the MRTFs and chromatin modifications at their target genes. Here we will establish the modifiers involved, the role played by the modifications in facilitating transcription, and their relation to chromatin modifications induced by the TCF proteins. Finally we are interested in elucidating how external environment determines the subcellular location of the MRTFs under resting conditions, and how MRTF/SRF signalling is linked to the effects of tissue mechanics on stem cell differentiation and the pro-tumorigenic activity of cancer associated fibroblasts.
Experience and competencies
This project will suit postdocs with research interests in gene regulation and a background in signal transduction, cancer biology, or cytoskeletal regulation. Postdocs are expected to lead their own projects, contribute to other projects on a collaborative basis. The ability to work in a team is essential.
- Experience in gene expression analysis techniques, including RNAseq and ChIPseq, and
- biochemistry, molecular biology or cell biology, or in the final stages of PhD submission
- Track record of publication, evidenced by published research papers or submitted manuscripts in refereed journals
- Excellent knowledge and understanding of the molecular biology of gene expression, cell signalling, and/or cytoskeletal dynamics
- Experience in biochemistry and protein purification
- Willingness to learn new experimental skills
- Good organisational skills, ability to work independently.
Esnault, C., Gualdrini, F., Horswell, S., Kelly, G., Stewart, A., East, P., Matthews, N., and Treisman, R. (2017). ERK-Induced Activation of TCF Family of SRF Cofactors Initiates a Chromatin Modification Cascade Associated with Transcription. Molecular cell 65, 1081-1095 e1085.
Esnault, C., Stewart, A., Gualdrini, F., East, P., Horswell, S., Matthews, N., and Treisman, R. (2014). Rho-actin signaling to the MRTF coactivators dominates the immediate transcriptional response to serum in fibroblasts. Genes & development 28, 943-958.
Foster, C.T., Gualdrini, F., and Treisman, R. (2017). Mutual dependence of the MRTF-SRF and YAP-TEAD pathways in cancer-associated fibroblasts is indirect and mediated by cytoskeletal dynamics. Genes & development 31, 2361-2375.
Gualdrini, F., Esnault, C., Horswell, S., Stewart, A., Matthews, N., and Treisman, R. (2016). SRF Co-factors Control the Balance between Cell Proliferation and Contractility. Molecular cell 64, 1048-1061.
Miralles, F., Posern, G., Zaromytidou, A.-I., and Treisman, R. (2003). Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113, 329-342.
Mylona, A., Theillet, F.X., Foster, C., Cheng, T.M., Miralles, F., Bates, P.A., Selenko, P., and Treisman, R. (2016). Opposing effects of Elk-1 multisite phosphorylation shape its response to ERK activation. Science 354, 233-237.
Olson, E.N., and Nordheim, A. (2010). Linking actin dynamics and gene transcription to drive cellular motile functions. Nat Rev Mol Cell Biol 11, 353-365.
Posern, G., and Treisman, R. (2006). Actin' together: serum response factor, its cofactors and the link to signal transduction. Trends Cell Biol 16, 588-596.
Vartiainen, M.K., Guettler, S., Larijani, B., and Treisman, R. (2007). Nuclear actin regulates dynamic subcellular localization and activity of the SRF cofactor MAL. Science 316, 1749-1752.