Position: Postdoctoral Research Fellow Project Title: Research in chromatin biochemistry Duration: One year initially with possibility of extension, candidate is expected to attract external postdoctoral funding Funding: BBSRC Supervisor: Dr Christian Speck, DNA Replication Group Location: Imperial College London, Hammersmith Campus Application Deadline: Open until filled Project Description The DNA Replication Group, Imperial College London, is looking to recruit a postdoctoral researcher interested in understanding how DNA replication factors promote heterochromatin formation and epigenetic memory. HP1 is a key constituent of heterochromatin. It promotes chromatin compaction and restricts access of regulatory factors to DNA. Misregulation of the HP1 chromatin interaction is associated with epigenetic disease, cancer and aging. How HP1 binds to chromatin is only partially understood, but of significant biological relevance. HP1 is made up of two conserved domains, the chromo domain and the chromoshadow domain, which are linked by a hinge region. HP1 recruitment to chromatin depends on a chromo domain interaction with a histone H3 that carries a trimethylation mark on lysine 9. Nevertheless, recently it was found that HP1 recruitment to chromatin also requires the origin recognition complex (ORC) proteins, which usually function in DNA replication. However, how ORC promotes HP1 recruitment to heterochromatin and its molecular function in transcription and role in disease is unknown. Our goal is to understand the mechanisms that promote accurate heterochromatin formation, as this represents the basis for epigenetic memory and genetic stability. We will investigate how ORC proteins influence HP1 recruitment to chromatin and if ORC alters HP1 dimerisation and oligomerisation on chromatin. We will identify structural changes in HP1 in response to ORC binding and in context of the nucleosome. Furthermore, we will investigate the genome-wide location of the HP1-ORC complexes and analyse the role of the complex in transcriptional regulation. Finally, we will explore if ORC-HP1 is involved in heterochromatin formation during oncogene induced senescence or in Friedreich's ataxia, a triplet expansion illness where hetero-chromatin induced down-regulation of frataxin gene (FXN) expression leads to a neurodegenerative phenotype in patients. These experiments address a key and largely unanswered question in chromatin biology: how is the spreading of heterochromatin regulated? By providing answers to these questions we will obtain a wide ranging understanding of many biological processes including the basis of epigenetic memory, which is disrupted during aging and disease. Thus, we expect that our work will have significant benefits for scientists and clinicians. This position will offer the candidate significant training opportunities, the chance to develop personally and professionally, a stimulating research environment and deep insights into chromatin biology and genome stability. Qualifications PhD with experience in chromatin biochemistry, molecular biology, structural biology and electron microsocpy We Offer • • The possibility to work on a cutting-edge project using state-of-the-art technology in a highly motivated research team A stimulating, diverse and international research environment • Advanced training opportunities, special seminar programs, tutorials on grant writing and career development Application Please send your application with curriculum vitae, letter of motivation and two references by e-mail to mailto:[email protected]. More information www.imperial.ac.uk/people/chris.speck http://www.specklab.com/ References Canzio, D., Larson, A., Narlikar, G. J. (2014). Mechanisms of functional promiscuity by HP1 proteins. Trends in Cell Biology 24, 377-386. Samel, S. A., Fernández-Cid, A., Sun, J., Riera, A., Tognetti, S., Herrera, C., Li, H., Speck, C. (2014). A unique DNA entry gate serves for regulated loading of the eukaryotic replicative helicase MCM2-7 onto DNA. Genes & Development 28, 16531666. Fernández-Cid, A.*, Riera, A.*, Tognetti, S., Herrera, M. C., Samel, S., Evrin, C., Winkler, C., Gardenal, E., Uhle. S., Speck, C. (2013). An ORC/Cdc6/MCM2-7 complex is formed in a multistep reaction to serve as a platform for MCM double-hexamer formation. Molecular Cell 50, 577-588. Sun, J., Evrin, C., Samel, S. A., Fernández-Cid, A., Riera, A., Kawakami, H., Stillman, B.*, Speck, C.*, Li. H.* (2013). Cryo-EM structure of a helicase loading intermediate containing ORC–Cdc6–Cdt1–MCM2-7 bound to DNA. Nature Structural & Molecular Biology 20, 944-951. *Corresponding authors Prasanth, S. G., Shen, Z., Prasanth, K. V., Stillman, B. (2010). Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization. Proceedings of the National Academy of Sciences of the United States of America 107, 15093-15098. Pak, D. T. S., Pflumm, M., Chesnokov, I., Huang, D. W., Kellum, R., Marr, J., Romanowski, P., Botchan, M. R. (1997). Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell 91, 311-323.
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