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英国帝国理工大学招聘染色质生物化学博士后
文章来源:知识人整理       更新时间:2014年08月27日

Postdoctoral position in Chromatin Biochemistry : London, United Kingdom

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.

Background:
HP1 is a key constituent of heterochromatin. HP1 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.

Description:
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.

Your qualifications: PhD
Position: The post is initially funded for one year with possibility for extension. The successful candidate is expected to attract an external postdoctoral Fellowship.
Research fields: Chromatin-biochemistry, Molecular Biology, Structural Biology, Electron Microscopy

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

Please send your application with the relevant documentation (CV, letter of motivation and two references) by email to: christian.speck@imperial.ac.uk

For more information on the group visit:
www.imperial.ac.uk/people/chris.speck
http://www.specklab.com/

References:

Pak DT, Pflumm M, Chesnokov I, Huang DW, Kellum R, Marr J, Romanowski P, Botchan MR. (1997) Association of the origin recognition complex with heterochromatin and HP1 in higher eukaryotes. Cell, Oct 31;91(3):311-23.

Prasanth SG, Shen Z, Prasanth KV, Stillman B. (2010). Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization. Proc Natl Acad Sci Aug 24;107 (34):15093-8.

Canzio D, Larson A, Narlikar GJ (2014) Mechanisms of functional promiscuity by HP1 proteins. Trends Cell Biology, 2014 Jun;24 (6):377-86.

Samel AS, Fernández-Cid A, Riera A, Tognetti S, Herrera MC, Speck C (2014). A unique DNA entry gate for regulated loading of the eukaryotic replicative helicase onto DNA. Genes & Development, Aug 28:1653-1666

Fernández-Cid A, Riera A, Tognetti S, Herrera MC, 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 MCM2-7 double-hexamer formation. Molecular Cell, 18 April, Volume 50, Issue 4, 577-588

Sun J, Evrin C, Samel S, Fernández-Cid A, Riera A, Kawakami H, Stillman B#, Speck C#, Li H# (2013). Architecture of the eukaryotic replication-licensing complex OCCM formed by ORC-Cdc6 and Cdt1-MCM2-7 on DNA. Nature Structure & Molecular Biology, August 5, (20), 944–951. # Corresponding author…

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