Jan 2020 – Jul 2023 Rosetrees grant
Funded by the Rosetrees Trust and Robert Luff Foundation (M906)
How endogenous viruses regulate the human immune system through epigenetic mechanisms
Long INterspersed Element 1s (LINE-1s) are the only active and autonomous transposable elements in the human genome. We have found them to be under tight epigenetic regulation by the HUSH complex and KAP1(TRIM28), and inactivation of the HUSH complex leads to a potent type I interferon response in normal primary human fibroblasts. Loss of the HUSH complex component, MPHOSPH8 (MPP8) also leads to derepression of a subset of long terminal repeats (LTRs) derived from endogenous retroviruses that are positioned proximal to interferon-response genes. Our Rosetrees grant is a pilot study aimed at investigating this pathway further in cancer cell lines and our Rosetrees work so far has linked HUSH-regulated LINE-1 elements to contributing to type I interferon responses, once their expression is resurrected (PMID: 33144593). This work is relevant to therapies aimed at awakening type I interferon responses to promote anti-tumour immunity and to shedding light on novel pathways driving inflammation.
May 2016 – December 2022
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 (derived from retroelements) have been beneficially repurposed in mammals to control gene regulatory networks. Through this work we have discovered that KRAB-zinc finger protein transcription factors regulate stage-specific genes by binding to cis-regulatory networks derived from retroelements.
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
This grant was focused on characterizing novel determinants of host gene regulation controlled through retroelement-derived sequences. Through this work, we uncovered the HUSH complex to be required for the silencing of LINE-1 elements early in development. Host genes repressed by this pathway include KRAB-zinc finger protein genes. Both TRIM28 and the HUSH complex are required to repress LINE-1 elements but they represent distinct pathways that recognize different molecular cues. In this work, we also investigated the conservation of the requirement for TRIM28 and the HUSH complex in regulation of retroelements and genes in human adult tissues. We uncovered a role for these pathways in the regulation of interferon-response genes.