The aim of this project is to understand how the recently identified antiviral HUSH complex and the antiviral protein REAF/RPRD2 can inhibit endogenous retroelements. Our preliminary data/working hypothesis suggest both act via epigenetic and post-transcriptional mechanisms, respectively. Genome embedded endogenous retroelements are evolutionary and functionally related to extant retroviruses, and so they are often susceptible to innate immune factors that can inhibit viruses. Equally, as major constituents of the genome, they are regulated by specific epigenetic means. When these processes are deregulated, this can lead to inflammatory autoimmune disease due to aberrant retroelement expression.
We and others have identified the HUSH complex and REAF/RPRD2 as able to repress the expression and mobility of endogenous retroelements, while both are also known to affect Human Immunodeficiency Virus (HIV) replication. However, the underlying molecular mechanism of inhibition is still not understood.
This project will use a range of molecular and cellular techniques to define how the HUSH complex and REAF/RPRD2 can control active human endogenous retroelements: LINE-1 and Alu retrotransposons. There will be particular emphasis on understanding protein-RNA interactions, and post-translational modifications. Full training will be given in a range of molecular approaches, cell culture, affinity proteomics, and confocal microscopy. The project will also use a range of sequencing technologies such as RNA-seq, ChIP-Seq and/or CLIP-Seq.
Understanding endogenous retroelement control in this manner will allow new insights regarding the role of genome elements in autoimmune disease.
Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Liu N, Lee CH, Swigut T, Grow E, Gu B, Bassik MC, Wysocka J.
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RNase H2, mutated in Aicardi-Goutières syndrome, promotes LINE-1 retrotransposition. Benitez-Guijarro M, Lopez-Ruiz C, Tamauskaite Z, Murina O, Mohammad MM, Williams TC, Fluteau A, Sanchez L, Vilar-Astasio R., Garcia-Cañadas M, Cano D, Kempen M-J, Sanchez-Pozo A, Heras SR, Jackson A, Reijns M, Garcia-Perez JL. EMBO Journal.2018. 37(15).
HIV-1 Vpr accessory protein interacts with REAF and mitigates its associated anti-viral activity. Gibbons JM, Marno KM, Pike R, Lee WY J, Jones CE, Fu RM, Bryan A, Ogunkolade BW, Pardieu C, Warnes G, Rowley PA, Sloan RD, McKnight Á. bioarXiv preprint server. 2018. doi: https://doi.org/10.1101/408161