Chromatin mediated control of retrotransposons

Lead Research Organisation: Newcastle University
Department Name: Inst for Cell and Molecular Biosciences

Abstract

Retrotransposons are mobile genetic elements which are found in the genomes of all eukaryotic organisms including humans. They are structurally and functionally related to retroviruses such as HIV and have the potential to be very harmful to the host organism because they may disrupt genes, alter their expression and can also drive genomic rearrangements. Indeed, occasionally retrotransposons can cause genetic disease and so all organisms must carefully control the expression of such elements. Therefore, the aims of this work are firstly, to study the mechanisms that control the expression of retrotransposons and secondly, to determine the outcomes when these controls are impaired. Retrotransposons that are related to those present in humans are also found in simple organisms such as yeast. Therefore, this study will use the fission yeast to study the control of retrotransposons as this unicellular organism is much easier to study and manipulate than complex multicellular organisms such as a humans.

Technical Summary

The expression of endogenous retrotransposons is tightly controlled as this is thought to be one mechanism that limits the potentially deleterious spread of these elements. While a number of studies have analysed the expression of retrotransposons at a global level there is very limited information relating to the regulation of individual elements. Therefore, we are currently using the fission yeast, Schizosaccharomyces pombe as a model system to analyze the regulation of individual retrotransposable elements. Our preliminary studies indicate that the basal expression of Tf2 retrotransposable elements is dependent upon their chromosomal context. Furthermore, the expression of at least a subset of these elements is repressed by the HIR/Asf1 nucleosome assembly factors and histone deacetylases suggesting that chromatin plays a key role in the regulation of these elements. Therefore, major objectives of this study are to dissect the regulatory mechanisms that control the expression of individual Tf2 elements and to characterise the chromatin structures that are associated with these elements. Further objectives are to determine whether disruption of chromatin leads to the mobilization of Tf2 retrotransposons and because retrotransposable elements are potential sources of genomic instability, to determine the role that chromatin plays in suppressing ectopic recombination between Tf2 elements.
 
Description Retrotransposons are mobile genetic elements which are found in the genomes of all eukaryotic organisms including humans. They are structurally and functionally related to retroviruses such as HIV and have the potential to be very harmful to the host organism because they may disrupt genes, alter their expression and can also drive genomic rearrangements. Indeed, occasionally retrotransposons can cause genetic disease and so all organisms must carefully control the expression of such elements. Therefore, the aims of this work are firstly, to study the mechanisms that control the expression of retrotransposons and secondly, to determine the outcomes when these controls are impaired. Retrotransposons that are related to those present in humans are also found in simple organisms such as yeast. Therefore, this study will use the fission yeast to study the control of retrotransposons as this unicellular organism is much easier to study and manipulate than complex multicellular organisms such as a humans.1. Our work revealed that the histone chaperone complex, HIRA plays a key role in the transcriptional silencing of Tf2/gypsy class LTR retrotransposons and their remnants in fission yeast.

2. An assay to measure the frequency of endogenous Tf2 mobilization events was established and the HIRA complex was found to restrict the spread of these elements in cells exposed to the stress imposed by low oxygen concentrations.

3 Tf2 elements were found not to function as intermolecular recombination hotspots either in wild type cells or in cells lacking the function of the HIRA complex. Thus it is unlikely that these elements are a major source of genomic instability.

LTR retrotransposons are present in the genomes of most eukaryotes (including those of mammals) and the HIRA histone chaperone is evolutionarily conserved. Thus our results have broad implications for the role of HIRA in control of LTR retrotransposons in other eukaryotic organisms.
Exploitation Route Enhance understanding of the regulation of retrotransposons and retroviruses.
Sectors Pharmaceuticals and Medical Biotechnology

 
Title LTR retrotransposition assay 
Description Creation of fission yeast strain that allows the mobilization frequency of endogenous LTR retrotransposon to measured 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? Yes  
Impact None as yet