Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes,Nature Cell Biology

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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes
Nature Cell Biology ( IF 21.3 ) Pub Date : 2023-01-12 , DOI: 10.1038/s41556-022-01056-x
Christina E Sparbier _{1,

2} , Andrea Gillespie ₁ , Juliana Gomez _{1,

3} , Nishi Kumari ₁ , 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 Popp ₃ , Daniel J Gough _{6,

7} , Melanie A Eckersley-Maslin _{1,

2,

8} , Sarah-Jane Dawson _{1,

2,

9} , Paul J Lehner ₁₀ , Kate D Sutherland _{11,

12} , Patricia Ernst _{13,

14} , Gerard M McGeehan ₁₅ , Enid Y N Lam _{1,

2} , Marian L Burr _{1,

2,

3,

16} , Mark A Dawson _{1,

2,

4,

9}

Affiliation

Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.
The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria, Australia.
Department of Molecular Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, Australia.
Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
Department of Anatomy and Physiology, University of Melbourne, Melbourne, Victoria, Australia.
Centre for Cancer Research, University of Melbourne, Melbourne, Victoria, Australia.
Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK.
ACRF Cancer Biology and Stem Cells Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Section of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Syndax Pharmaceuticals, Waltham, MA, USA.
Department of Anatomical Pathology, ACT Pathology, Canberra Health Services, Canberra, Australian Capital Territory, Australia.

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.

中文翻译：

靶向 Menin 破坏 KMT2A/B 和 polycomb 平衡以自相矛盾地激活二价基因

在二价启动子处精确控制激活 H3K4me3 和抑制 H3K27me3 组蛋白修饰对于正常发育至关重要，并且在癌症中经常被破坏。通过将二价 MHC I 类基因表达的细胞表面读数与全基因组 CRISPR-Cas9 筛选相结合，我们确定了 MTF2-PRC2.1、PCGF1-PRC1.1 和 Menin-KMT2A/B 复合物在维持二价性方面的特定作用。Menin 的遗传缺失或药理学抑制出乎意料地表型复制了多梳破坏的影响，导致癌细胞和多能干细胞中二价基因的去阻遏。虽然 Menin 和 KMT2A/B 在活性基因上对 H3K4me3 有贡献，但 KMT2A/B 的独立的 Menin 独立功能维持 H3K4me3 并反对 polycomb 介导的二价基因抑制。Menin 靶向后活性基因中 KMT2A 的释放改变了二价基因上 polycomb 和 KMT2A 的平衡，促进了基因激活。Menin-KMT2A/B 复合物成分的这种功能划分揭示了可以通过抑制 Menin 来利用的治疗机会。

更新日期：2023-01-13

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