@article{359e1f5afd0f46c89b3f39e2240bda99,
title = "Chromatin remodeling of histone H3 variants by DDM1 underlies epigenetic inheritance of DNA methylation",
abstract = "Nucleosomes block access to DNA methyltransferase, unless they are remodeled by DECREASE in DNA METHYLATION 1 (DDM1LSH/ HELLS), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 promotes replacement of histone variant H3.3 by H3.1. In ddm1 mutants, DNA methylation is partly restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The sin gle-particle cryo-EM structure at 3.2 A˚ of DDM1 with a variant nucleosome reveals engagement with histone H3.3 near residues required for assembly and with the unmodified H4 tail. An N-terminal autoinhibitory domain inhibits activity, while a disulfide bond in the helicase domain supports activity. DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1Dnmt1, but is blocked by H4K16 acetylation. The male germline H3.3 variant MGH3/HTR10 is resistant to remodeling by DDM1 and acts as a placeholder nucleosome in sperm cells for epigenetic inheritance. ",
author = "Lee, {Seung Cho} and Adams, {Dexter W} and Ipsaro, {Jonathan J.} and Jonathan Cahn and Jason Lynn and Hyun-Soo Kim and Benjamin Berube and Viktoria Major and Calarco, {Joseph P.} and Chantal LeBlanc and Sonali Bhattacharjee and Umamaheswari Ramu and Daniel Grimanelli and Yannick Jacob and Philipp Voigt and Leemor Joshua-Tor and Martienssen, {Robert A}",
note = "Funding Information: We thank Crisanto Gutierrez for providing H3.1-GFP and H3.3-RFP Arabidopsis reporter lines and Fr{\'e}d{\'e}ric Berger for providing the htr4 htr5 htr8/+ and HTR13-CFP lines. We thank Eric Richards, Vincent Colot, and Tetsuji Kakutani for discussions on the genetics of ddm1, and Cigall Kadoch, Filipe Borges, and Jean-Sebastien Parent for helpful advice. We thank Joe Calarco (in memoriam) for the anti-DDM1 polyclonal antibodies. We acknowledge technical assistance for live imaging from Nour El-Amine, and informatics help from Leandro Quadrana (Ecole Normale Superieur, France). Research in the Martienssen laboratory is supported by the U.S. National Institutes of Health (NIH) grant R01 GM067014, the National Science Foundation Plant Genome Research Program, and the Howard Hughes Medical Institute. The authors acknowledge assistance from the Cold Spring Harbor Laboratory Shared Resources, which are funded in part by a Cancer Center Support grant (5PP30CA045508). This work was also supported by grant #R35GM128661 from the National Institutes of Health to Y.J. the Wellcome Trust ([104175/Z/14/Z], Sir Henry Dale Fellowship to P.V.) and through funding from the UK Biotechnology and Biological Sciences Research Council (BBS/E/B/000C0421) and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (ERC-STG grant agreement no. 639253 to P.V.). The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust (203149). We are grateful to the Edinburgh Protein Production Facility (EPPF) and to Dennis Thomas at the Cold Spring Harbor Laboratory cryo-EM facility for their support. The EPPF was supported by the Wellcome Trust through a Multi-User Equipment grant (101527/Z/13/Z). L.J. and R.A.M. are Investigators of the Howard Hughes Medical Institute. S.C.L. L.J. and R.A.M. designed the study. S.C.L. J.J.I. D.W.A. J.L. H.-S.K. U.R. C.L. S.B. and V.M. performed the experiments. J.C. S.C.L. J.J.I. D.W.A. B.B. D.G. Y.J. L.J. and R.A.M. analyzed the data and/or its significance. S.C.L. and R.A.M. wrote the manuscript with contributions from J.C. J.J.I. and Y.J. P.V. L.J. and R.A.M. acquired funding. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: We thank Crisanto Gutierrez for providing H3.1-GFP and H3.3-RFP Arabidopsis reporter lines and Fr{\'e}d{\'e}ric Berger for providing the htr4 htr5 htr8/+ and HTR13-CFP lines. We thank Eric Richards, Vincent Colot, and Tetsuji Kakutani for discussions on the genetics of ddm1, and Cigall Kadoch, Filipe Borges, and Jean-Sebastien Parent for helpful advice. We thank Joe Calarco (in memoriam) for the anti-DDM1 polyclonal antibodies. We acknowledge technical assistance for live imaging from Nour El-Amine, and informatics help from Leandro Quadrana (Ecole Normale Superieur, France). Research in the Martienssen laboratory is supported by the U.S. National Institutes of Health (NIH) grant R01 GM067014 , the National Science Foundation Plant Genome Research Program , and the Howard Hughes Medical Institute . The authors acknowledge assistance from the Cold Spring Harbor Laboratory Shared Resources, which are funded in part by a Cancer Center Support grant ( 5PP30CA045508 ). This work was also supported by grant # R35GM128661 from the National Institutes of Health to Y.J., the Wellcome Trust ([ 104175/Z/14/Z ], Sir Henry Dale Fellowship to P.V.) and through funding from the UK Biotechnology and Biological Sciences Research Council ( BBS/E/B/000C0421 ) and the European Research Council (ERC) under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (ERC-STG grant agreement no. 639253 to P.V.). The Wellcome Centre for Cell Biology is supported by core funding from the Wellcome Trust ( 203149 ). We are grateful to the Edinburgh Protein Production Facility (EPPF) and to Dennis Thomas at the Cold Spring Harbor Laboratory cryo-EM facility for their support. The EPPF was supported by the Wellcome Trust through a Multi-User Equipment grant ( 101527/Z/13/Z ). L.J. and R.A.M. are Investigators of the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = sep,
day = "14",
doi = "10.1016/j.cell.2023.08.001",
language = "English",
volume = "186",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "19",
}