May 2016 – December 2021
European Research Council starting grant, TransposonsReprogram (678350):
How retrotransposons remodel the genome during early development and reprogramming
The overall goal of our ERC starting grant is to understand how DNA-sequences of viral origin have been beneficially repurposed in mammals to allow normal progression through development. Viruses are ideal tools that the cell can repurpose as regulatory hubs because they contain compact promoters, enhancers and silencers within a short long terminal repeat (LTR) sequence, for example, and mounting evidence shows that some of these ancient viruses are switched on in early development. We hypothesize that transposon-derived DNA sequences have evolved to play essential roles in cell fate transitions in early development and during reprogramming. We are using several novel zinc finger protein transcription factors that bind to transposon DNA as tools to explore the function of these transposons. We are modelling cell fate transitions by using naïve embryonic stem cell differentiation into neural progenitor cells, as well as reprogramming assays.
Understanding these new mechanisms of regulation of developmental genes is important because it will help us to direct stem cell fate and to control reprogramming of committed cells back into induced pluripotent stem cells, which is relevant to making more effective stem cell therapies. More broadly, this research will help us to understand how genetic mutations within non-coding regions of the genome can lead to developmental diseases in which transposons are implicated, such as Repeat Expansion Disorders or Aicardi Goutières Syndrome.
September 2013 – January 2020
Sir Henry Dale Fellowship, funded by the Royal Society and Wellcome Trust, UK (101200/Z/13/Z):
Epigenetic pathways through which endogenous retroviruses regulate cellular genes in pluripotent cells
Little is understood about the mechanisms by which regulatory hubs derived from endogenous viruses act as enhancers or repressors for cellular genes. Our research programme, which is jointly funded by the Wellcome Trust and Royal Society is concerned with characterizing the nuts and bolts of how epigenetic complexes regulate cellular genes by binding to ancient viral-derived DNA sequences. Our work is based in pluripotent embryonic stem cells, which serve as a model of early development, and in these cells, we and others have identified endogenous retroviruses that can act as enhancers and some that can act as repressors. We are characterizing which transcription factors are bound to these elements and pursuing mechanism by using knockout and rescue experiments and reporter assays.
In parallel, we assess if epigenetic pathways we discover to be important in embryonic stem cells, still contribute to retroviral silencing in adult somatic cells. Epigenetic control of transposons in adult tissues is of particular interest to us because reactivation of nucleic acids or proteins encoded by transposons that are not usually expressed could stimulate an innate or adaptive immune response if they are recognised as non-self by the immune system. There is mounting evidence that epigenetic pathways are particularly important in maintaining retroviral silencing in some cancers such as colorectal or ovarian cancers and inactivating these pathways can promote tumour clearance, partly through reactivation of endogenous retroviruses and their production of double-stranded RNAs, resulting in a type I interferon response through RNA sensing. Our fundamental research on the mechanics of retroviral silencing in pluripotent and somatic cells is therefore relevant for the field of cancer immunotherapy and will also feed into our understanding of autoimmune diseases, in which transposons are implicated, such as systemic lupus erythematosus.