Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes

Sparbier, CE; Gillespie, A; Gomez, J; Kumari, N; Motazedian, A; Chan, KL; Bell, CC; Gilan, O; Chan, YC; Popp, S; Gough, DJ; Eckersley-Maslin, MA; Dawson, SJ; Lehner, PJ; Sutherland, KD; Ernst, P; McGeehan, GM; Lam, EYN; Burr, ML; Dawson, MA

Author(s): Sparbier, CE; Gillespie, A; Gomez, J; Kumari, N; Motazedian, A; Chan, KL; Bell, CC; Gilan, O; Chan, YC; Popp, S; Gough, DJ; Eckersley-Maslin, MA; Dawson, SJ; Lehner, PJ; Sutherland, KD; Ernst, P; McGeehan, GM; Lam, EYN; Burr, ML; Dawson, MA;
Details: Publication Year 2023-01-12,Volume 25,Issue #2,Page 258-272
Journal Title: Nature Cell Biology
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 function of KMT2A/B maintains H3K4me3 and opposes polycomb-mediated repression at bivalent genes. Release of KMT2A from active genes following Menin targeting alters the balance of polycomb and KMT2A at bivalent genes, facilitating gene activation. This functional partitioning of Menin-KMT2A/B complex components reveals therapeutic opportunities that can be leveraged through inhibition of Menin.
Publisher: NPG
Keywords: Polycomb-Group Proteins/genetics; Transcription Factors/genetics; Genome; Pluripotent Stem Cells; Promoter Regions, Genetic
Research Division(s): Cancer Biology And Stem Cells
PubMed ID: 36635503
Link To PubMed Central Version: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7614190/
Publisher's Version: https://doi.org/10.1038/s41556-022-01056-x
Open Access at Publisher's Site: https://doi.org/ 10.1038/s41556-022-01056-x
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-02-27 10:36:14

Last Modified: 2023-03-06 01:24:52