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

Christina E Sparbier; Andrea Gillespie; Juliana Gomez; Nishi Kumari; Ali Motazedian; Kah Lok Chan; Charles C Bell; Omer Gilan; Yih-Chih Chan; Sarah Popp; Daniel J Gough; Melanie A Eckersley-Maslin; Sarah-Jane Dawson; Paul J Lehner; Kate D Sutherland; Patricia Ernst; Gerard M McGeehan; Enid Y N Lam; Marian L Burr; Mark A Dawson

doi:10.1038/s41556-022-01056-x

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

Nat Cell Biol. 2023 Feb;25(2):258-272. doi: 10.1038/s41556-022-01056-x. Epub 2023 Jan 12.

Authors

Christina E Sparbier^{1

2}, Andrea Gillespie¹, Juliana Gomez^{1

3}, Nishi Kumari¹, Ali Motazedian^{1

2}, Kah Lok Chan^{1

2

4}, Charles C Bell^{1

2}, Omer Gilan^{1

5}, Yih-Chih Chan^{1

2}, Sarah Popp³, Daniel J Gough^{6

7}, Melanie A Eckersley-Maslin^{1

2

8}, Sarah-Jane Dawson^{1

2

9}, Paul J Lehner¹⁰, Kate D Sutherland^{11

12}, Patricia Ernst^{13

14}, Gerard M McGeehan¹⁵, Enid Y N Lam^{1

2}, Marian L Burr^#^{16

17

18

19}, Mark A Dawson^#^{20

21

22

23}

Affiliations

¹ Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
² Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
³ The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
⁴ Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁵ Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
⁶ Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
⁷ Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
⁸ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
⁹ Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
¹⁰ Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
¹¹ ACRF Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹² Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
¹³ Section of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁴ Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁵ Syndax Pharmaceuticals, Waltham, MA, USA.
¹⁶ Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. marian.burr@anu.edu.au.
¹⁷ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. marian.burr@anu.edu.au.
¹⁸ The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia. marian.burr@anu.edu.au.
¹⁹ Department of Anatomical Pathology, ACT Pathology, Canberra Health Services, Canberra, Australian Capital Territory, Australia. marian.burr@anu.edu.au.
²⁰ Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. mark.dawson@petermac.org.
²¹ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia. mark.dawson@petermac.org.
²² Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia. mark.dawson@petermac.org.
²³ Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia. mark.dawson@petermac.org.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Genome
Pluripotent Stem Cells*
Polycomb-Group Proteins / genetics
Promoter Regions, Genetic
Transcription Factors* / genetics

Substances

Polycomb-Group Proteins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding