DAXX adds a de novo H3.3K9me3 deposition pathway to the histone chaperone network

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A multitude of histone chaperones are required to support histones from their biosynthesis until DNA deposition. They cooperate through the formation of histone co-chaperone complexes, but the crosstalk between nucleosome assembly pathways remains enigmatic. Using exploratory interactomics, we define the interplay between human histone H3–H4 chaperones in the histone chaperone network. We identify previously uncharacterized histone-dependent complexes and predict the structure of the ASF1 and SPT2 co-chaperone complex, expanding the role of ASF1 in histone dynamics. We show that DAXX provides a unique functionality to the histone chaperone network, recruiting histone methyltransferases to promote H3K9me3 catalysis on new histone H3.3–H4 prior to deposition onto DNA. Hereby, DAXX provides a molecular mechanism for de novo H3K9me3 deposition and heterochromatin assembly. Collectively, our findings provide a framework for understanding how cells orchestrate histone supply and employ targeted deposition of modified histones to underpin specialized chromatin states.

OriginalsprogEngelsk
TidsskriftMolecular Cell
Vol/bind83
Udgave nummer7
Sider (fra-til)1075-1092.e9
Antal sider28
ISSN1097-2765
DOI
StatusUdgivet - 2023

Bibliografisk note

Funding Information:
We thank Nadezhda T. Doncheva and Lars J. Jensen for help with cytoscape, Alberto García-Nieto for preliminary results, and A.G. and M.L.N. lab members for helpful discussions. M.L.N. is supported by the Independent Research Fund Denmark ( 0135-00096B and 8020-00220B ), the European Union’s Horizon 2020 research and innovation program under grant agreement EPIC-XS-823839 , and the Danish Cancer Society ( R146-A9159-16-S2 ). A.G. is supported by the European Research Council (ERC CoG 724436 ), the Lundbeck Foundation ( R198-2015-269 and R313-2019-448 ), the Independent Research Fund Denmark ( 7016-00042B ) and the Novo Nordisk Foundation ( NNF21OC0067425 ). Research at CPR is supported by the Novo Nordisk Foundation ( NNF14CC0001 ). A.I. is supported by the Deutsche Forschungsgemeinschaft (DFG CRC1064-213249687 and CRC1309-325871075 ). G.M. is supported by Novo Nordisk Foundation grants ( NNF0024386 and NNF17SA00302140 ), a Distinguished Investigator Award ( NNF18OC0055061 ), and is part of the Integrative Structural Biology Cluster (ISBUC) at the University of Copenhagen . The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust ( 203149 ).

Funding Information:
We thank Nadezhda T. Doncheva and Lars J. Jensen for help with cytoscape, Alberto García-Nieto for preliminary results, and A.G. and M.L.N. lab members for helpful discussions. M.L.N. is supported by the Independent Research Fund Denmark (0135-00096B and 8020-00220B), the European Union's Horizon 2020 research and innovation program under grant agreement EPIC-XS-823839, and the Danish Cancer Society (R146-A9159-16-S2). A.G. is supported by the European Research Council (ERC CoG 724436), the Lundbeck Foundation (R198-2015-269 and R313-2019-448), the Independent Research Fund Denmark (7016-00042B) and the Novo Nordisk Foundation (NNF21OC0067425). Research at CPR is supported by the Novo Nordisk Foundation (NNF14CC0001). A.I. is supported by the Deutsche Forschungsgemeinschaft (DFG CRC1064-213249687 and CRC1309-325871075). G.M. is supported by Novo Nordisk Foundation grants (NNF0024386 and NNF17SA00302140), a Distinguished Investigator Award (NNF18OC0055061), and is part of the Integrative Structural Biology Cluster (ISBUC) at the University of Copenhagen. The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust (203149). A.G. M.C. and C.M.H. conceived the study, designed experiments, and wrote the manuscript with input from all authors. M.C. led the interactome characterization of the histone chaperones and DAXX-mediated histone supply. M.C. performed the final proteomics data analysis in consultation with I.A.H. C.M.H. performed label-free histone pull-downs and related data analysis. AlphaFold predictions were performed by C.M.H. in consultation with M.W. and G.M. I.A.H. and J.D.E. designed MS methodology, acquired the majority of SILAC and label-free MS data, and performed preliminary MS data analysis, all in consultation with M.L.N. M.V.-A. and V.S.-M. acquired and analyzed histone PTMs MS in consultation with A.I. C.S. acquired mass spectrometry data in consultation with J.R. C.M.H. and A.G. are inventors on a patent covering the therapeutic targeting of TONSL for cancer therapy. A.G. is co-founder and chief scientific officer of Ankrin Therapeutics. A.G. is a member of Molecular Cell's Scientific Advisory Board. A.I. and M.V.-A. are cofounders of EpiQMAx. G.M. is co-founder and member of the board of directors of Twelve Bio and is a member of the Scientific Advisory Board at Ensoma. We support inclusive, diverse, and equitable conduct of research.

Publisher Copyright:
© 2023 The Author(s)

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