biostudies-literatureUnknownLee SCEuropean Research CouncilNCI NIH HHSWellcome TrustNIGMS NIH HHSEpigenetic 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 <i>ddm1</i> 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 assemblbioRxiv : the preprint server for biology2023.07.11.548598https://www.ebi.ac.uk/biostudies/studies/S-EPMC10369972biostudies-literatureChromatin remodeling of histone H3 variants underlies epigenetic inheritance of DNA methylation.PMC10369972P30 CA045508R01 GM067014104175/Z/14/ZR35 GM128661639253101527/Z/13/ZMajor VBerube BJacob YKim HSMartienssen RALee SCCalarco JPLeBlanc CJoshua-Tor LCahn JVoigt PGrimanelli DAdams DWLynn JRamu UIpsaro JJBhattacharjee SfalseChromatin remodeling of histone H3 variants underlies epigenetic inheritance of DNA methylation.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 <i>ddm1</i> 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 assembl2023-01-01T00:00:00Z2023 Aug2026-06-22T03:18:06.671Z2025-02-19T01:18:04.021ZS-EPMC103699723750314310.1101/2023.07.11.548598