Lee, Seung Cho, Adams, Dexter W, Ipsaro, Jonathan J, Cahn, Jonathan, Lynn, Jason, Kim, Hyun-Soo, Berube, Benjamin, Major, Viktoria, Calarco, Joseph P, LeBlanc, Chantal, Bhattacharjee, Sonali, Ramu, Umamaheswari, Grimanelli, Daniel, Jacob, Yannick, Voigt, Philipp, Joshua-Tor, Leemor, Martienssen, Robert A (August 2023) Chromatin remodeling of histone H3 variants underlies epigenetic inheritance of DNA methylation. bioRxiv. (Submitted)
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Abstract
Epigenetic inheritance refers to the faithful replication of DNA methylation and histone modification independent of DNA sequence. Nucleosomes block access to DNA methyltransferases, unless they are remodeled by DECREASE IN DNA METHYLATION1 (DDM1 Lsh/HELLS ), a Snf2-like master regulator of epigenetic inheritance. We show that DDM1 activity results in replacement of the transcriptional histone variant H3.3 for the replicative variant H3.1 during the cell cycle. In ddm1 mutants, DNA methylation can be restored by loss of the H3.3 chaperone HIRA, while the H3.1 chaperone CAF-1 becomes essential. The single-particle cryo-EM structure at 3.2 Å of DDM1 with a variant nucleosome reveals direct engagement at SHL2 with histone H3.3 at or near variant residues required for assembly, as well as with the deacetylated H4 tail. An N-terminal autoinhibitory domain binds H2A variants to allow remodeling, while a disulfide bond in the helicase domain is essential for activity in vivo and in vitro . We show that differential remodeling of H3 and H2A variants in vitro reflects preferential deposition in vivo . DDM1 co-localizes with H3.1 and H3.3 during the cell cycle, and with the DNA methyltransferase MET1 Dnmt1 . DDM1 localization to the chromosome is blocked by H4K16 acetylation, which accumulates at DDM1 targets in ddm1 mutants, as does the sperm cell specific H3.3 variant MGH3 in pollen, which acts as a placeholder nucleosome in the germline and contributes to epigenetic inheritance.
| Item Type: | Paper |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > epigenetics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > epigenetics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein methylation > histone methylation |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Joshua-Tor lab CSHL labs > Martienssen lab School of Biological Sciences > Publications |
| SWORD Depositor: | CSHL Elements |
| Depositing User: | CSHL Elements |
| Date: | 2 August 2023 |
| Date Deposited: | 19 Sep 2023 15:13 |
| Last Modified: | 29 Feb 2024 19:31 |
| PMCID: | PMC10369972 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/40907 |
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