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

• Published in: Nature communications 2024-06, Vol.15 (1), p.4883-15
• Main Authors: Zhang, Yi, Xie, Guojia, Lee, Ji-Eun, Zandian, Mohamad, Sudarshan, Deepthi, Estavoyer, Benjamin, Benz, Caroline, Viita, Tiina, Asgaritarghi, Golareh, Lachance, Catherine, Messmer, Clémence, Simonetti, Leandro, Sinha, Vikrant Kumar, Lambert, Jean-Philippe, Chen, Yu-Wen, Wang, Shu-Ping, Ivarsson, Ylva, Affar, El Bachir, Côté, Jacques, Ge, Kai, Kutateladze, Tatiana G.
• Format: Article
• Language: English
• Subjects: 101/6; 13/1; 140/131; 45/15; 45/70; 631/208/176; 631/45/612/100; 631/535/878/1263; 82/83; Animals; Binding; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Embryo cells; Embryogenesis; Embryonic growth stage; Enhancer Elements, Genetic; Enhancers; HEK293 Cells; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones; Histones - metabolism; Humanities and Social Sciences; Humans; Methyltransferase; Mice; Molecular modelling; multidisciplinary; PHD Zinc Fingers; Polycomb group proteins; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Stem cells; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Ubiquitin Thiolesterase - genetics; Ubiquitin Thiolesterase - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-49391-x

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. Human methyltransferase MLL4 mediates embryonic development and is dysregulated in diseases. Zhang et al. found that binding of PHD fingers of MLL4 to ASXL1/2 is required for recruitment of the deubiquitinase BAP1 to MLL4-bound active enhancers in vitro.