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NIDDK, NIH

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Nat. Commun., Jun 07 2024, 15 (1) 4883 | https://doi.org/10.1038/s41467-024-49391-x ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers

Yi Zhang^1,8,9, Guojia Xie^2,9, Ji-Eun Lee^2,9, Mohamad Zandian^1,9, Deepthi Sudarshan^3,9, Benjamin Estavoyer⁴, Caroline Benz⁵, Tiina Viita³, Golareh Asgaritarghi³, Catherine Lachance³, Clémence Messmer⁴, Leandro Simonetti⁵, Vikrant Kumar Sinha¹, Jean-Philippe Lambert³, Yu-Wen Chen⁶, Shu-Ping Wang⁶, Ylva Ivarsson⁵, El Bachir Affar^4,7, Jacques Côté³, Kai Ge² & Tatiana G. Kutateladze¹

¹Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.

²Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD 20892, USA.

³St-Patrick Research Group in Basic Oncology, Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center, Quebec City, QC G1R 3S3, Canada.

⁴Maisonneuve-Rosemont Hospital Research Center, Montréal, QC H1T 2M4, Canada.

⁵Department of Chemistry, BMC, Uppsala University, Uppsala 75237, Sweden.

⁶Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC.

⁷Department of Medicine, University of Montréal, Montréal, QC H3C 3J7, Canada.

⁸Present address: Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.

⁹These authors contributed equally: Yi Zhang, Guojia Xie, Ji-Eun Lee, Mohamad Zandian, Deepthi Sudarshan.

Corresponding authors

Correspondence to Jacques Côté, Kai Ge or Tatiana G. Kutateladze.

Abstract

The human methyltransferase and transcriptional coactivator MLL4 and its paralog MLL3 are frequently mutated in cancer. MLL4 and MLL3 monomethylate histone H3K4 and contain a set of uncharacterized PHD fingers. Here, we report a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL4 and MLL3 that bind to ASXL2, a component of the Polycomb repressive H2AK119 deubiquitinase (PR-DUB) complex. The structure of MLL4 PHD2/3 in complex with the MLL-binding helix (MBH) of ASXL2 and mutational analyses reveal the molecular mechanism which is conserved in homologous ASXL1 and ASXL3. The native interaction of the Trithorax MLL3/4 complexes with the PR-DUB complex in vivo depends solely on MBH of ASXL1/2, coupling the two histone modifying activities. ChIP-seq analysis in embryonic stem cells demonstrates that MBH of ASXL1/2 is required for the deubiquitinase BAP1 recruitment to MLL4-bound active enhancers. Our findings suggest an ASXL1/2-dependent functional link between the MLL3/4 and PR-DUB complexes.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-23)
연구진국외 연구진
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