Aims of the lab
Each of our cells contains the same genome, the same set of instructions, but exhibit wildly different morphologies and functions. We are interested in how RNA acts together with chromatin modifiers and transcription factors to specify different cell types and how this goes wrong in disease. We primarily use embryonic stem cells as a model for embryonic development and T helper cells as a model for adult cell differentiation and our research is underpinned by our expertise in genomics and molecular biology methods.
Although primarily considered to be a passive intermediary, we have demonstrated that pre-mRNA is a regulatory molecule. We have found that pre-mRNA contains G-quadruplex (G4) forming elements that directly interact with the repressive chromatin regulator PRC2 and blocks its recruitment to active genes. We have also identified additional chromatin and transcriptional regulators for which interaction with chromatin is inhibited by nascent RNA. We hypothesise that through interactions with regulatory proteins, pre-mRNAs and other nascent transcripts provide direct feedback from transcriptional output to chromatin state. We are currently seeking to understand the role of these mechanisms in cell differentiation and the maintenance of cell identity.
PRC2 function is often dysregulated in cancer, either due to gene deletion, gene overexpression, point mutations or gene fusion events. Around 50% of cases of low-grade endometrial stromal sarcoma exhibit fusion of the gene encoding the PRC2 subunit SUZ12 with the gene encoding the NuA4-associated protein JAZF1. We have discovered that this fusion protein lacks interaction with specific PRC2 accessory factors, alters PRC2 gene occupancy and histone modification, and disrupts gene expression and cell differentiation. We currently working to understand the role of enhancer RNAs in oncogene activation and whether G4 RNA can be used to evict PRC2 from tumour-suppressor genes.
The ability of T helper cells to differentiate into diverse effector lineages allows tailoring of the immune response to different pathogens. Modulation of effector T cell state may also enhance the immune response to cancer. We have determined how the lineage-determining transcription factor T-bet drives differentiation into the Th1 effector lineage, the effect of inflammatory disease-associated genetic variants on T-bet function and identified ways to block T-bet-mediated immune gene activation. We are currently applying the same strategies to identify the factors that control the differentiation of tumour-infiltrating T lymphocytes.
Selected publications and pre-prints
Tavares M, Khandelwal G, Muter J, Viiri K, Beltran M, Brosens JJ, Jenner RG. (2022). JAZF1-SUZ12 dysregulates PRC2 function and gene expression during cell differentiation. Cell Rep.39: 110889. https://doi.org/10.1016/j.celrep.2022.110889.
Hertweck A, Vila de Mucha M, Barber PR, Dagil R, Porter H, Ramos A, Lord GM, Jenner RG. (2022). The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes. Nucleic Acids Res. 50(8):4557-4573. doi: 10.1093/nar/gkac258.
Lo JWP, Vila de Mucha M, Roberts LB, Garrido-Mesa N, Hertweck A, Neves JF, Stolarczyk E, Henderson S, Jackson I, Howard JK, Jenner RG*, Lord GM*. (2022). A population of CD4+ T cells with a naïve phenotype stably polarized to the Th1 lineage. Eur. J. Immunol. 52(4):566-581. doi: 10.1002/eji.202149228.
Skalska L, Begley V, Beltran M, Lukauskas S, Khandelwal G, Faull P, Bhamra A, Tavares M, Wellman R, Tvardovskiy A, Foster BM, Ruiz de los Mozos R, Herrero J, Surinova S, Snijders AP, Bartke T, Jenner RG. (2021). Nascent RNA antagonises the interaction of a set of regulatory proteins with chromatin. Mol Cell. 81: 2944-2959.e10. doi: https://doi.org/10.1016/j.molcel.2021.05.026.
Śledzińska A, Vila de Mucha M, Bergerhoff K, Hotblack A, Franz Demane D, Ghorani E, Arakrca A, Marzolini MAV, Solomon I, Arce Vargas F, Pule M, Ono M, Seddon B, Kassiotis G, Marafioti T, Ariyan CE, Korn T, Lord GM, Stauss H, Jenner RG, Peggs KS*, Quezada SA*. (2020). Regulatory T cells restrain IL-2- and Blimp-1-dependent acquisition of cytotoxic function by CD4+ T cells. Immunity 52:151-166.
Beltran M, Tavares M, Justin N, Khandelwal G, Ambrose A, Foster BM, Worlock K, Tvardovskiy A, Kunzelmann S, Herrero J, Bartke T, Gamblin SJ, Wilson JR, Jenner RG. (2019). G-tract RNA removes Polycomb Repressive Complex 2 from genes. Nat Struct Mol Biol. 26:899-909.
Skalska L, Beltran M, Ule J, Jenner RG. (2017). Regulatory feedback from nascent RNA to chromatin and transcription. Nat Rev Mol Cell Biol. 18:331-337.
Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG*, Lord GM*. (2017). Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. PLOS Genet. 13:e1006587
Beltran M, Yates CM, Skalska L, Dawson M, Reis FP, Viiri K, Fisher CL, Sibley CR, Foster BM, Bartke T, Ule J, Jenner RG. (2016). The interaction of PRC2 with RNA or chromatin is mutually antagonistic. Genome Res 26: 896-907.
Hertweck A, Evans CM, Eskandarpour M, Lau JCH, Oleinika K, Jackson I, Kelly A, Ambrose J, Adamson P, Cousins D, Lavender P, Calder VL, Lord GM, Jenner RG. (2016). T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell Rep. 15: 2756–2770.
Bouwman RD, Palser A, Parry CM, Coulter E, Rasaiyaah R, Kellam P, Jenner RG. (2014). Human immunodeficiency virus Tat associates with a specific set of cellular RNAs. Retrovirology 11: 53.
Kanhere A, Hertweck A, Bhatia U, Gokmen R, Perucha, E, Jackson I, Lord GM, Jenner RG. (2012). T-bet and GATA3 orchestrate Th1 and Th2 cell differentiation through lineage-specific targeting of distal regulatory elements. Nature Communications. 3:1268.
Kanhere A, Viiri K, Araújo CC, Rasaiyaah J, Bouwman RD, Whyte WA, Pereira CF, Brookes E, Walker K, Bell GW, Pombo A, Fisher AG, Young RA, Jenner RG (2010). Short RNAs are transcribed from repressed Polycomb target genes and interact with Polycomb Repressive Complex-2. Mol Cell. 38:675-688.