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Establishing an insect model for epigenetic diseases

Primary Supervisor: Dr Eamonn Mallon, Department of Genetics and Genome Biology

Secondary supervisor: Dr Flaviano Giorgini

PhD project title: Establishing an insect model for epigenetic diseases

University of Registration: University of Leicester

Project outline:

Epigenetics is defined as the heritable change in expression of a gene without any change in the DNA sequence. It is important in fields as diverse as human cancer biology and the ecological response of animals and plants to environmental pollutants. The methylation of the fifth position of DNA’s cytosine’s ring is one of the most widespread epigenetic markers.

The study of epigenetics has for the most part been correlational. A common correlational research strategy is to examine the methylation differences between two phenotypes and hypothesise that the differences found are the causes of the phenotype. What is rarer is a strategy analogous to reverse genetics, whereby the methylation of an organism is changed, and the resultant phenotype studied to confirm methylation’s role.

Until recently, what reverse epigenetics there has been of a general, crude sort. For example, early studies of the role of methylation in mammalian development, simply knocked out DMNT3, the enzyme responsible for the production of new methylation marks. This reduced the methylation throughout the embryo’s genome and the resultant phenotype was measured. Other studies decreased total genomic methylation by the use of drugs such as 5-aza-2’-deoxycytidine. This has now all changed with the use of the CRISPR system to alter the methylation levels at a single locus.

Simple insect models are needed to understand complicated biological processes. The parasitic wasp Nasonia vitripennis is a prime contender as an insect model species for epigenetics. The fruit fly, Drosophila melanogaster, has long been the predominant insect model for genetics. However, Drosophila, for the most part, lacks CpG methylation. Nasonia, like other hymenoptera, has a functional methylation system. Nasonia replicates many of the abilities of the Drosophila model, namely it is easily maintained in a laboratory environment due to its short generation time (approximately 2 weeks) and ease of rearing. Its genome has been sequenced and many molecular tools are now available for this species. Recently, CRISPR/Cas9 technology has been used to induce site specific mutations on the cinnabar (cinnabar) gene in N. vitripennis adding a new powerful molecular tool for reverse genetics for this insect.

In this project you will identify candidate genes for various epigenetic diseases. You will then alter their methylation status using CRISPR technology and record their phenotype using a series of assays.

Merely as an example, consider cancer. The development of human cancer is a multistep process, involving changes in signalling, cell-cycle and cell-death pathways, as well as interactions between the tumour and the tumour microenvironment. To dissect the steps of tumorigenesis, simple animal models, such as insect models are needed. Changes in methylation are a fundamental part of cancer development. This project will develop a system to allow changes in methylation status on a given gene in an insect model. This could lead to an insect model for cancer epigenomics, a major step forward in the field.

Mukherjee et al (2015) Insects as models to study the epigenetic basis of disease, Progress in Biophysics and Molecular Biology, Volume 118, Issues 1–2, Pages 69-78.

BBSRC Strategic Research Priority: Sustainable Agriculture and Food: Animal Health and Welfare. Integrated Understanding of Health: Ageing & Diet and Health

Techniques that will be undertaken during the project:

  • Bioinformatics
  • Cloning
  • Transgenics
  • qpcr
  • Minos and Behavioural assays

Contact: Dr Eamonn Mallon, University of Leicester