Transgenerational Epigenetic Inheritance & Evolution

Lead Research Organisation: MRC Clinical Sciences Centre

Abstract

Transposons are “selfish” genomic parasites that hitchhike within the genomes of most animals. Left uncontrolled, they can interfere with its function, so organisms have evolved mechanisms to keep them in check. However, when transposons move around within genomes they can shuffle parts of the host genome at the same time, and sometimes these changes prove beneficial. Thus organisms might not silence transposons completely because this would stifle their potential to adapt to new environments. This means that the mechanisms that silence transposons must themselves be kept in check to avoid over-zealous silencing. Maintaining this balance is critical- for example it seems to go wrong in diseases such as cancer, where transposons are more active than normal. We are using nematode worms as a model system to study how transposon silencing is regulated. In these simple animals, with a lifespan of only a few days, we manipulate transposon silencing pathways and track what happens to their genomes over many generations. Moreover, many nematode species have lost one very important transposon silencing mechanism (the “piRNA” pathway- a type of small RNA molecule that recognises transposon RNAs and targets them for destruction), so we use nematodes as a natural experiment to study the long-term consequences of losing transposon silencing mechanisms. In this way we hope to learn how transposon regulation affects evolution, and how this may influence the development of cancer.

Technical Summary

Transposons, parasitic DNA segments that can copy themselves independently of the replication of their host genome, are abundant across metazoan organisms. Left unchecked, transposons pose a severe threat to genome integrity, thus organisms have evolved robust mechanisms in order to keep transposons in check. However, transposons are also an important source of genetic diversity, with many examples now documented of how transposon insertions lead to potentially beneficial genetic changes to organisms- indeed up to 40% of primate-specific gene regulatory elements are thought to have originated in this way. Thus the mechanisms that control transposons may themselves be regulated to ensure that they do not completely stifle transposon activity, thereby removing an important source of evolutionary novelty. We are interested in how this delicate balance is maintained, and whether it can be altered in order to facilitate adaptation of organisms to the environment.
To address the question of how transposon silencing mechanisms are regulated to control the origin of evolutionary novelty we are using nematodes as a model system. Our main focus is piwi-interacting small RNAs (piRNAs), a transposon silencing pathway that is active in the germline and is conserved across metazoans. Just as in drosophila and mammal, piRNAs in the model nematode C. elegans are able to silence transposons and are important in maintaining the fertility of the animal over many generations. In addition, piRNAs are capable of establishing epigenetic changes that can be inherited for many generations independently of the presence of the initial piRNA trigger. However, we recently discovered that piRNAs are not found universally across the nematode phylum. In fact the entire piRNAs pathway is has been lost several times independently in different nematode lineages. Moreover, even in C. elegans, we showed in collaboration with Shawn Ahmed (University of North Carolina), that the loss of fertility that occurs in animals lacking the piRNA pathway can be completely suppressed by mutations compromising insulin signalling pathways.
These two unusual aspects of the nematode piRNA system mean that nematodes offer a unique advantage to study what happens to genome evolution in the absence of the piRNA pathway. By using comparative genomics between different nematode species we are trying to decipher the effects of piRNAs on long-term genome evolution. Moreover, we are using in lab evolution in C. elegans to test in the short term what happens to genome evolution in the absence of the piRNA pathway. Together these two approaches will enable us to answer the fundamental questions of how transposons contribute to evolutionary novelty, and how cellular epigenetic pathways influence this process. Moreover, our work will give insight into the ways in which aberrant transposon silencing, as is known to occur in cancer, may contribute to the development of the disease.
 
Description Imperial College Junior Research Fellowship
Amount £77,757 (GBP)
Organisation Imperial College London (ICL) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2015 
End 09/2018
 
Description Research Project Grant
Amount
Funding ID RPG-2016-210 
Organisation The Leverhulme Trust 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 08/2016 
End 08/2019
 
Description Analysis of the contribution made by small RNAs to speciation in nematodes 
Organisation Hong Kong Baptist University
Department Department of Chemistry
Country Hong Kong, Special Administrative Region of China 
Sector Academic/University 
PI Contribution We sequenced and analysed small RNAs from introgression lines between two closely related nematode species that have hybrid inviability
Collaborator Contribution Construction of introgression lines and phenotypic characterisation
Impact Multi-disciplinary: evolutionary biology, molecular biology, bioinformatics Publication in Genome Research on which Sarkies is joint corresponding author
Start Year 2014
 
Description Epigenetics of Parhyale hawaiensis (model crustacean) 
Organisation University of Oxford
Department Oxford Centre for Magnetic Resonance
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Bisulfite sequencing of Parhyale animals in order to identify genome-wide DNA methylation profile. Analysis of this data
Collaborator Contribution Dr Aziz Aboobaker provided material for Parhyale DNA methylation analysis and provided discussion about analysis results as well as sequencing the genome which we were then given access to in order interpret the results
Impact The genome of Parhyale was published in Elife and the DNA methylation analysis was included in the genome. This is expected to be a high-impact paper as there will be many groups interested in using this crustacean as a model for regeneration.
Start Year 2016
 
Description Evolution of RNAi in arthropods 
Organisation University of Cambridge
Department Department of Chemistry
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Academic/University 
PI Contribution Currently providing supervision in bioinformatic analysis of small RNA sequencing of various arthropod species and directly developing new methods to analyse data, as well as contributing to the strategic guidance of the project as a whole and analysing a part of the dataset myself. Hosting Dr Sam Lewis in my laboratory for several one to two day visits and communicating regularly with him by Skype as well as with the co-supervisors.
Collaborator Contribution Frank Jiggins: (University of Cambridge) Resources for small RNA sequencing, co-supervision of Dr Lewis, strategic guidance for the project Eric Miska: (University of Cambridge) Resources for small RNA sequencing including sequencing costs, co-supervision and strategic guidance
Impact We have produced a comprehensive analysis of arthropod small RNAs with some important discoveries, many of which are completely unexpected and will adjust the views of the field as a whole. This work will be published, likely in a high impact journal.
Start Year 2016
 
Description Article on MRC LMS website 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I wrote a brief summary of the paper I had recently published in Genome Research explaining the significance of the work and its potential implications, and with the help of the public engagement specialists at the LMS (Susan Watts and team) this was mounted on the website and allowed the general public to get an insight into this research.
Year(s) Of Engagement Activity 2016
URL http://csc.mrc.ac.uk/csc-researchers-latest-findings/
 
Description Workshop, Young Biologists Association, Armenia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact I participated in a workshop on epigenetics organised by the Young Biologists Association in Yerevan Armenia. The workshop was primarily aimed at undergraduate and postgraduate students. I introduced theories and up-to-date techniques in a lecture and chaired a focussed discussion group. The workshop stimulated interest in the subject and participants reported that they had improved their understanding of the subject through attending the course.
Year(s) Of Engagement Activity 2015
URL http://www.yba.am/index.php?page=ShowAnnounItem&lang=Eng&id=101