Journal article
Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes
CE Sparbier, A Gillespie, J Gomez, N Kumari, A Motazedian, KL Chan, CC Bell, O Gilan, YC Chan, S Popp, DJ Gough, MA Eckersley-Maslin, SJ Dawson, PJ Lehner, KD Sutherland, P Ernst, GM McGeehan, EYN Lam, ML Burr, MA Dawson
Nature Cell Biology | NATURE PORTFOLIO | Published : 2023
Abstract
Precise control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent promoters is essential for normal development and frequently corrupted in cancer. By coupling a cell surface readout of bivalent MHC class I gene expression with whole-genome CRISPR–Cas9 screens, we identify specific roles for MTF2–PRC2.1, PCGF1–PRC1.1 and Menin–KMT2A/B complexes in maintaining bivalency. Genetic loss or pharmacological inhibition of Menin unexpectedly phenocopies the effects of polycomb disruption, resulting in derepression of bivalent genes in both cancer cells and pluripotent stem cells. While Menin and KMT2A/B contribute to H3K4me3 at active genes, a separate Menin-independent..
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Awarded by Snow Medical
Funding Acknowledgements
\We thank the Peter MacCallum Cancer Centre Molecular Genomics Core and the flow cytometry facility. We thank the following funders for fellowship, scholarship and grant support: Snow Medical Research Foundation Fellowship (M.L.B. and M.E.-M.), Cancer Research UK Clinician Scientist Fellowship C53779/A20097 and NHMRC Investigator Grant 1196598 (M.L.B.), Sir Edward Dunlop Fellowship, Cancer Council of Victoria, NHMRC Investigator Grant 1196749 and Howard Hughes Medical Institute International Research Scholarship 55008729 (M.A.D.), CSL Centenary Fellowship and NHMRC Investigator Grant 1196755 (S.-J.D.), Peter and Julie Alston Centenary fellowship (K.D.S.), Wellcome Trust Principal Research Fellowship 101835/Z/13/Z (P.J.L.), Peter MacCallum Postgraduate Scholarship (C.E.S.), NHMRC Postgraduate Scholarship (K.L.C.), Maddie Riewoldt's Vision 064728 (Y.-C.C.), Victorian Cancer Agency (E.Y.N.L.), VCA Mid-Career Fellowship MCRF19033 (D.J.G.), CSL Centenary Fellowship (S.-J.D.) and NHMRC grants 1164054 and 2010275 (M.L.B.), 1085015 and 1106444 (M.A.D.), and 1128984 (M.A.D. and S.-J.D.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Schematics in Fig. 1a,d, Fig. 4b and Extended Data Fig. 10a were created with BioRender.com.