Stem cells, Cancer, Ageing, RNA modifications
Description of Research
Epitranscriptomics, the modulation of RNA function via its chemical modification, has emerged as a pervasive new mechanism of gene regulation. The role of the epitranscriptome on stem cell fate, maintenance and ageing remains largely unexplored. Similarly, the impact of aberrant RNA modification and editing on oncogenic transformation and cancer stem cell maintenance remains poorly investigated, however early studies suggest that the modification of RNA could be exploited for the development of new therapies for devastating diseases including anti-leukaemia therapies.
My group investigates the relevance of RNA modifications in normal and malignant stem cell biology, with a focus on haematopoiesis. Using sophisticated CRISPR screening platforms, I have identified a significant number of epitranscriptomic vulnerabilities of acute myeloid leukaemia (AML) and have gone on to investigate some of these in detail, including the m6A writer METTL3 (Barbieri et al, Nature, 2017) and the m7G writer METTL1 (Orellana et al, Mol Cell, 2021). Notably, our latest study of the first-in-class METTL3 inhibitor (Yankova et al, Nature, 2021) provides strong proof-of-concept that RNA-modifying enzymes represent a new avenue for anti-cancer therapeutics.
Future aims include study of selected RNA modifying enzymes which I identified as essential for either normal or leukaemic haematopoietic stem cells and whose function is currently unknown or incompletely understood with a particular focus on how particular RNA modifications regulate cell fate, differentiation, ageing and leukaemogenesis in normal and malignant haematopoiesis.
Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, Pilka ES, Aspris D, Leggate D, Hendrick AG, Webster NA, Andrews B, Fosbeary R, Guest P, Irigoyen N, Eleftheriou M, Gozdecka M, Dias JML, Bannister AJ, Vick B, Jeremias I, Vassiliou GS, Rausch O, Tzelepis K*, Kouzarides T*. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021 May;593(7860):597-601. *Joint corresponding authors
Orellana EA, Liu Q, Yankova E, Pirouz M, De Braekeleer E, Zhang W, Lim J, Aspris D, Sendinc E, Garyfallos DA, Gu M, Ali R, Gutierrez A, Mikutis S, Bernardes GJL, Fischer ES, Bradley A, Vassiliou GS, Slack FJ, Tzelepis K*, Gregory RI*. METTL1-mediated m7G modification of Arg-TCT tRNA drives oncogenic transformation. Mol Cell. 2021 Aug 19;81(16):3323-3338.e14. *Joint corresponding authors
Yankova E, Aspris D, Tzelepis K. The N6-methyladenosine RNA modification in acute myeloid leukemia. Curr Opin Hematol. 2021 Mar 1;28(2):80-85.
Han N*, Hwang W*, Tzelepis K*, Schmerer P, Yankova E, MacMahon M, Lei W, M Katritsis N, Liu A, Felgenhauer U, Schuldt A, Harris R, Chapman K, McCaughan F, Weber F, Kouzarides T. Identification of SARS-CoV-2-induced pathways reveals drug repurposing strategies. Sci Adv. 2021 Jun 30;7(27):eabh3032. *Joint first authors
Mikutis S, Gu M, Sendinc E, Hazemi ME, Kiely-Collins H, Aspris D, Vassiliou GS, Shi Y, Tzelepis K*, Bernardes GJL*. meCLICK-Seq, a Substrate-Hijacking and RNA Degradation Strategy for the Study of RNA Methylation. ACS Cent Sci. 2020 Dec 23;6(12):2196-2208. *Joint corresponding authors
Tzelepis K, Rausch O, Kouzarides T. RNA-modifying enzymes and their function in a chromatin context. Nat Struct Mol Biol. 2019 Oct;26(10):858-862.
Tzelepis K*, De Braekeleer E, Aspris D, Barbieri I, Vijayabaskar MS, Liu WH, Gozdecka M, Metzakopian E, Toop HD, Dudek M, Robson SC, Hermida-Prado F, Yang YH, Babaei-Jadidi R, Garyfallos DA, Ponstingl H, Dias JML, Gallipoli P, Seiler M, Buonamici S, Vick B, Bannister AJ, Rad R, Prinjha RK, Marioni JC, Huntly B, Batson J, Morris JC, Pina C, Bradley A, Jeremias I, Bates DO, Yusa K*, Kouzarides T*, Vassiliou GS*. SRPK1 maintains acute myeloid leukemia through effects on isoform usage of epigenetic regulators including BRD4. Nat Commun. 2018 Dec 19;9(1):5378. *Joint corresponding authors
Barbieri I*, Tzelepis K*, Pandolfini L*, Shi J, Millán-Zambrano G, Robson SC, Aspris D, Migliori V, Bannister AJ, Han N, De Braekeleer E, Ponstingl H, Hendrick A, Vakoc CR, Vassiliou GS, Kouzarides T. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017 Dec 7;552(7683):126-131. *Joint first authors
Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, Mupo A, Grinkevich V, Li M, Mazan M, Gozdecka M, Ohnishi S, Cooper J, Patel M, McKerrell T, Chen B, Domingues AF, Gallipoli P, Teichmann S, Ponstingl H, McDermott U, Saez-Rodriguez J, Huntly BJP, Iorio F, Pina C, Vassiliou GS, Yusa K. Cell Rep. 2016 Oct 18;17(4):1193-1205.