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. 听
G-tract elements with nascent pre-mRNA remove PRC2 from chromatin
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.
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Loss of the SUZ12 N terminus prevents interaction of JAZF1-SUZ12 with EPOP, PALI1, and JARID2, decreasing PRC2 occupancy and reducing H3K27me3 at polycomb target genes. Fusion to JAZF1 induces association with NuA4/TIP60 and increases H4Kac at these sites. These changes are mirrored by ectopic activation of polycomb target genes in hEnSCs, inducing part of the decidualization gene expression program that lacks activation of immune response genes associated with clearance of senescent decidual cells from the endometrium
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.
Hertweck A, Vila de Mucha M, Barber PR, Dagil R, Porter H, Ramos A, Lord GM, Jenner RG. (2022). . 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 na茂ve 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). . Mol Cell. 81: 2944-2959.e10. doi: .
艢ledzi艅ska A, Vila de MuchaM, Bergerhoff听K, Hotblack听A, Franz Demane听D,Ghorani听E, Arakrca听A,Marzolini听MAV, Solomon听I,Arce Vargas听F, Pule听M, Ono听M, Seddon听B, Kassiotis听G, Marafioti听T, Ariyan听CE, Korn听T, Lord听GM, Stauss听H, JennerRG, PeggsKS*, Quezada听SA*. (2020). . Immunity52:151-166.
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,听Jenner RG. (2019). . Nat Struct Mol Biol. 26:899-909.
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). . 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).听. Genome Res 26: 896-907.听
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.听 (2016).听. Cell Rep. 15: 2756鈥�2770.听
Bouwman RD, Palser A, Parry CM, Coulter E, Rasaiyaah R, Kellam P, Jenner RG. (2014). . Retrovirology 11: 53.
Kanhere A, Hertweck A, Bhatia U, Gokmen R, Perucha, E, Jackson I, Lord GM, Jenner RG. (2012).听. Nature Communications. 3:1268.
Kanhere A, Viiri K, Ara煤jo CC, Rasaiyaah J, Bouwman RD, Whyte WA, Pereira CF, Brookes E, Walker K, Bell GW, Pombo A, Fisher AG, Young RA, Jenner RG (2010).听. Mol Cell. 38:675-688.
Contact
Richard Jenner, MA PhD Professor of Molecular Biology 香港六合彩 Cancer Institute University College London Paul O鈥橤orman Building 72 Huntley Street London WC1E 6BT.
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