Abstract
JADE is a core subunit of the HBO1 acetyltransferase complex that regulates developmental and epigenetic programs and promotes gene transcription. Here we describe the mechanism by which JADE facilitates recruitment of the HBO1 complex to chromatin and mediates its enzymatic activity. Structural, genomic and complex assembly in vivo studies show that the PZP (PHD1–zinc-knuckle–PHD2) domain of JADE engages the nucleosome through binding to histone H3 and DNA and is necessary for the association with chromatin targets. Recognition of unmethylated H3K4 by PZP directs enzymatic activity of the complex toward histone H4 acetylation, whereas H3K4 hypermethylation alters histone substrate selectivity. We demonstrate that PZP contributes to leukemogenesis, augmenting transforming activity of the NUP98–JADE2 fusion. Our findings highlight biological consequences and the impact of the intact JADE subunit on genomic recruitment, enzymatic function and pathological activity of the HBO1 complex.
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Data availability
Coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 8GDX and 8GE0. All other relevant data supporting the key findings of this study are available within the paper, its Supplementary Information or from the corresponding authors upon reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank H. Sato, I. Yokoyama, K. Ito, E. Kanai and A. Yokoyama for technical assistance. This work was supported in part by grants from the National Institutes of Health: HL151334, GM135671, GM125195, CA252707 and AG067664 to T.G.K., GM131626 and GM139564 to M.G.P., from the Japan Society for the Promotion of Science (JSPS) KAKENHI grants (22H03109 and 22KK0119) to A.Y. and A.K. and from the Canadian Institutes of Health Research (CIHR) (FDN-143314, PJT-178367) to J.C. This work was also supported in part by research funds to A.Y. from the Yamagata prefectural government and the city of Tsuruoka.
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N.G., A.K., C.L., K.L.C., J.L., A.T.G., N.S., B.J.K., Y.K. and S.A. performed experiments and, together with A.J.R., M.G.P., J.C., A.Y. and T.G.K., analyzed the data. A.Y. and T.G.K. wrote the paper with input from all authors.
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Nature Structural & Molecular Biology thanks Jun Qin and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Primary Handling Editors: Sara Osman and Carolina Perdigoto, in collaboration with the Nature Structural & Molecular Biology team.
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ChIP–seq tags, ChIP–qPCR, expression and colony-forming data.
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Gaurav, N., Kanai, A., Lachance, C. et al. Guiding the HBO1 complex function through the JADE subunit. Nat Struct Mol Biol (2024). https://doi.org/10.1038/s41594-024-01245-2
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DOI: https://doi.org/10.1038/s41594-024-01245-2