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Epigenetic control in regulating oncogenic nucleic acid structures and cell fate specification

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  • Full or part time
    Dr R.A. Chen
  • Application Deadline
    Applications accepted all year round

Project Description

Our main research interest is to understand the mechanistic action of epigenetic control in common human diseases. We aim to identify and characterise the conserved regulatory circuits underlie human diseases including the onset of human cancer. Therefore, in addition to mammalian tissue culture cells, we use the powerful genetic model organism C. elegans to study conserved regulatory events at the chromatin level. These round worms (nematodes) share 70% of proteins encoded in the human genome. Most proteins involved in transcription and chromatin function are highly conserved. The comprehensive genetic tools (e.g. the genome-wide RNAi library), short life cycle (only 3 days), and the ease of molecular experiments (e.g. CRISPR genome editing) make C. elegans a great experimental system to address basic biological questions. In parallel, we are also using tissue culture cells to aid the understanding of the underlying mechanisms for human diseases.    

CpG-rich promoters are frequently present across the C. elegans and human genome. These widely active genomic regions have been found to harbour highly occupied target (HOT) regions for transcription factors (Chen et al., 2014 Genome Research). It suggests that CpG island promoters can function as regulatory hubs for chromatin regulators and consequently may modulate transcriptional activities and other genomic events. CFP-1 is an evolutionarily conserved epigenetic regulator that binds to CpG-rich promoters in both humans and C. elegans. CFP-1 is part of the COMPASS complex that contains the major transferase for histone 3 lysine 4 tri-methylation (H3K4me3); SET-2 in C. elegans and SETD1A in humans. H3K4me3 is frequently found in active promote regions that are highly accessible (a.k.a. HOT regions) to allow frequent transcription firing. Nevertheless, the roles of H3K4me3 in gene expression and the formation of HOT regions are largely unclear. To address these key questions in epigenetic control, we are characterising cfp-1 and set-2 loss-of-function C. elegans mutants for their ability in inducing gene expression, specifying cell fate, and modulating chromatin architectures. In parallel, we are also "translating" our C. elegans findings into murine myoblast/osteoblast cells using CRISPRi and shRNA tools to investigate the role of epigenetic control in oncogenic nucleic acid structures, and cell fate decisions.

We are inviting a junior researcher to join our exciting, dynamic and international research team. We strongly support Equality, Diversity and Inclusion in Science and Health Research.

Our lab website: www.ronchenlab.info

Funding Notes

http://www.leeds.ac.uk/info/130541/university_scholarships_and_funding/247/leeds_doctoral_scholarships

References

Chen RAJ, Stempor P, Down TA, Zeiser E, Feuer SK, Ahringer J Extreme HOT regions are CpG-dense promoters in C. elegans and humans Genome Research 24 1138-1146, 2014
DOI:10.1101/gr.161992.113

Chen RAJ, Down TA, Stempor P, Chen QB, Egelhofer TA, Hillier LDW, Jeffers TE, Ahringer J The landscape of RNA polymerase II transcription initiation in C. elegans reveals promoter and enhancer architectures. Genome Research 23 1339-1347, 2013
DOI:10.1101/gr.153668.112




How good is research at University of Leeds in Biological Sciences?

FTE Category A staff submitted: 60.90

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