英国弗郎西斯奎克研究院2020年招收博士后

Postdoctoral Training Fellow JD

This is a full-time 4yr fixed-term position on Crick terms and conditions of employment.

The Treisman research group

Work in the Signalling and Transcription group focusses on the SRF transcription factor network, a major nuclear targets of Rho and Ras signalling, two major signalling pathways involved in oncogenic transformation, invasion and metastasis. Our main interest 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, Nat Rev Mol Cell Biol 2010; Posern and Treisman, TIBS 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.

The group usually comprises 2-3 postdoctoral research fellows and 2-3 graduate students, supported by 3 postdoctoral level research assistants. Details of research projects currently being undertaken can be seen at:

https://www.crick.ac.uk/research/a-z-researchers/researchers-t-u/richard-treisman/

Project – Molecular mechanisms of MRTF-SRF signalling

The Myocardin-Related Transcription Factors (MRTF-A and MRTF-B) couple SRF activity to Rho signalling induced by growth factors or mechanical stress (Olson and Nordheim, 2010; Posern and Treisman, 2006). They act as sensors of cellular G-actin level, binding G-actin through their regulatory RPEL domain, which controls MRTF subcellular localisation and transcriptional activity (Miralles et al., Cell 2003; Mouilleron et al., Sci. Sig.2011). Studies by us and others have shown that MRTF-SRF signalling is required for cell adhesion, migration, and experimental metastasis (Medjkane et al., Genes Dev 2009), and in some cases, for transformation (Muehlich et al., Oncogene 2012). Cancer development and progression are accompanied by increased tissue stiffening, and in contractile and invasion-promoting cancer-associated fibroblasts (CAFs), MRTF-SRF signalling plays a critical role (Foster et al., Genes Dev. 2017).

We previously have defined the direct genomic targets for the SRF, and shown that Rho-actin signalling is a major contributor to the fibroblast growth factor response (Esnault et al., Genes Dev. 2014). We characterised the kinetics of ERK-induced TCF phosphorylation (Mylona et al., Science 2016). We evaluated the contribution of the TCFs to the transcriptional and chromatin response to response to ERK activation, showing that their activation is required for histone modifications at the TSS (Esnault et al., Mol. Cell 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., Mol. Cell 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., Genes Dev. 2017).

We are particularly 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., Cell 2003). Our previous studies have shown that nuclear G-actin suppresses MRTF target gene transcription (Vartiainen et al., Science 2007).

Our recent data shows that this involves control both of MRTF-SRF interaction and gene targeting, and RNA polymerase II recruitment and initiation, and 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

Postdoctoral Training Fellows are expected to lead their own projects, contribute to other projects on a collaborative basis (both in the lab and with external collaborators) and guide PhD students in their research. The ability to work in a team is essential.

The post holder should embody and demonstrate our core Crick values: bold, imaginative, open, dynamic and collegial, in addition to the following:

Essential

PhD. in 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 with gene expression analysis techniques, including RNAseq and ChIPseq, and their analysis

Experience in biochemistry and protein purification

Willingness to learn new experimental skills

Good organisational skills, ability to work independently and to prioritise workload

Desirable

Experience with cell biology and microscopy techniques

Experience and facility with DNA manipulation

Experience in bioinformatics and gene expression analysis

Effective written and verbal communication skills

Ability to communicate with others where English is not the first language