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Investigating the genetic regulatory circuits of aberrant DNA structures leading to human cancer

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Aberrant DNA structures can cause instability of the genome, leading to the mutations and gross chromosome rearrangements typical of cancer cells (1). Complex regulatory events linked with the DNA structures play a fundamental role in numerous biological events. These structures can impact on genomic activities including DNA replication and transcription. Therefore, it’s crucial to improve our understanding of the formation and resolution of such pathological DNA structures.

DNA warps around nucleosomes composed of histones to form chromatin in all eukaryotic cells. Chromatin structure can be shaped by the interplay between DNA structures and nucleosome occupancy. Chromatin regulation plays a key role in various biological processes such as DNA replication, repair and transcription. Our recent findings have shown that HOT (high-occupancy target) regions are bound by a surprisingly large number of transcription factors and found to display high levels of chromatin accessibility and CpG-rich sequences in both human and C. elegans (2). The high accessibility of DNA may be caused by a specific DNA structure that disfavours the occupancy of nucleosomes. Also, these highly accessible DNAs may be susceptible to DNA damage leading to the formation of genetic variants. This idea is supported by a recent report showing that genetic risk variants are enriched in HOT regions in both disease-relevant and cancer cells (3). Therefore, it is essential to understand the formation and role of DNA structures and their relevance in human diseases.

C. elegans is an excellent model to study the genetic regulatory circuits and molecular mechanisms that underlie human diseases. The high level of protein conservation and the ease of molecular experiments make C. elegans a powerful model system to identify and characterise novel gene function relevant to human diseases. To mechanistically dissect the role of DNA structures, we will mainly use C. elegans but also use mammalian cells in parallel. This PhD project is a collaborative work between Drs. Ron Chen’s and Edwin Chen’s research teams. It will apply functional genetic and genomic assays plus molecular and biochemical approaches. Applicants with a strong interest in genetics/molecular biology are encouraged to apply; especially those with previous research experiences in genetic screens and/or C. elegans.

If you wish to enquire further details of the project informally, please contact Dr. Ron Chen, email:

Lab websites for the two groups are:
Dr. Ron Chen: http://www.ronchenlab.info
Dr. Edwin Chen: http://www.edwinchenlab.com

Funding Notes

The studentship is funded only for UK and EU applicants.

Ideally the starting date would be in the Spring or Summer Term 2017 (Jan or April 2017).

References

(1) Chen et al., Cell reports 13:2345-2352 (2015)
(2) Chen et al., Genome Research 24(7):1138-1146 (2014)
(3) Li et al., Scientific Reports (5):11633 (2015)

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

FTE Category A staff submitted: 60.90

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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