ASXLs binding to the PHD2/3 fingers of MLL4 provides a mechanism for the recruitment of BAP1 to active enhancers

Yi Zhang, Guojia Xie, Ji-Eun Lee, Mohamad Zandian, Deepthi Sudarshan, Benjamin Estavoyer, Caroline Benz, Tiina Viita, Golareh Asgaritarghi, Catherine Lachance, Clémence Messmer, Leandro Simonetti, Vikrant Kumar Sinha, Jean-Philippe Lambert, Yu-Wen Chen, Shu-Ping Wang, Ylva Ivarsson, El Bachir Affar, Jacques Côté (), Kai Ge () and Tatiana G. Kutateladze ()
Additional contact information
Yi Zhang: University of Colorado School of Medicine
Guojia Xie: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Ji-Eun Lee: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Mohamad Zandian: University of Colorado School of Medicine
Deepthi Sudarshan: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Benjamin Estavoyer: Maisonneuve-Rosemont Hospital Research Center
Caroline Benz: Uppsala University
Tiina Viita: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Golareh Asgaritarghi: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Catherine Lachance: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Clémence Messmer: Maisonneuve-Rosemont Hospital Research Center
Leandro Simonetti: Uppsala University
Vikrant Kumar Sinha: University of Colorado School of Medicine
Jean-Philippe Lambert: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Yu-Wen Chen: Academia Sinica
Shu-Ping Wang: Academia Sinica
Ylva Ivarsson: Uppsala University
El Bachir Affar: Maisonneuve-Rosemont Hospital Research Center
Jacques Côté: Oncology Division of CHU de Québec-Université Laval Research, Laval University Cancer Research Center
Kai Ge: National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Tatiana G. Kutateladze: University of Colorado School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49391-x

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