Project ID CM-HD2024_47


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Immunology & Microbial Sciences, Peter Gorer Department of ImmunobiologyWebsite

Epigenetic control of naivety in human infants

Individual cell types are specialized to undertake tasks determined by the gene repertoire they are capable of expressing. This expression profile, in turn, is determined by the epigenetic landscapes generated during cellular differentiation. We and others have established that naive T cells isolated from either neonates or adults have markedly distinct expression of an RNA encoding IGF2BP3. We have determined that this differential is maintained at the protein level. IGF2BP3 encodes an RNA-binding protein believed to recognize methylated RNA transcripts. Using RNA Immunoprecipitation and RNAseq, we identified numerous transcripts bound by IGF2BP3, where approximately 50% of these encoded transcriptional or epigenetic regulators. Indeed, epigenetic landscapes of adult and UBC naïve T cells were markedly different as measured by either DNA methylation, ATAC seq or H3K4me3 ChIPseq. This PhD programme will focus upon the role that IGF2BP3 plays in shaping the epigenetic landscape and subsequently the immune function of naïve neonatal cells and seek to determine how and why this function is diminished in adult naïve cells.

Our initial focus will be to test IGF2BP3 function in naïve T cells by manipulating IGF2BP3 expression via inhibitors of IGF2BP3 and/or by virus-mediated knockdown. We will assay epigenetic landscapes using ATACseq, ChIPseq and DNA methylation, the transcriptome by RNAseq and effector functions of these cells by in vitro activation and flow cytometry to identify the effect of reduced IGF2BP3 expression.

As IGF2BP3 binds to methylated (m6A) RNA, we will next address whether IGF2BP3-targeted methylated RNAs in UBC naïve T cells remain methylated in naïve T cells during the lifecourse.

Thirdly, we will address whether elevated IGF2BP3 expression is a feature of other immune cell types in neonates.

We will conduct these experiments during years 1 and 2 of the project leaving the final year to explore avenues arising from the newly acquired data.

Representative Publications

Villiers W, Kaufmann-Cook J, Kelly A, He X, Elbasir A, Bensmail H, Lavender P, Dillon R, Mifsud B, Osborne CS. 2023. Multi-omics and machine learning reveal context-specific gene regulatory activities of PML-RARA in Acute Promyelocytic Leukemia. Nature Communications. In press. Switzer CH, Cho HJ, Eykyn TR, Lavender P & Eaton P. 2022. NOS2 and S-nitrosothiol signaling induces DNA hypomethylation and LINE-1 retrotransposon expression. PNAS 119(21), e2200022119. McErlean P, Kelly A, Dhariwal J, Kirtland M, Watson J, Smith J, Saxena A Cousins D, Solari R, Van Oosterhout A, Edwards MR, Johnston SL and Lavender P. 2020. Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium. Frontiers in Genetics.;11:585746. doi: 10.3389/fgene.2020.585746.
Gee S, Chandiramani M, Seow J, Pollock E, Modestini C, Das A, Tree T, Doores KJ, Tribe RM, Gibbons DL. The legacy of maternal SARS-CoV-2 infection on the immunology of the neonate. Nat Immunol. 2021 Dec;22(12):1490-1502. doi: 10.1038/s41590-021-01049-2. Kamdar S, Hutchinson R, Laing A, Stacey F, Ansbro K, Millar M, Costeloe K, Wade W, Fleming P, Gibbons DL. Perinatal Inflammation Influences but Does Not Arrest Rapid Immune Development in Preterm Babies Nat Commun 11, 1284 (2020).