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RIF1 regulates post-replicative H3K9me3 restoration at multiple cell cycle stages

ABSTRACT: DNA replication causes the dilution of parental histones with their specific post-translational modification. The kinetics of restoration of these marks on the newly incorporated histones dictates how quickly genomic domains re-acquire their epigenetic identity after replication. H3K9me3 is reconstituted extremely slowly: only in the following S-phase, just prior to replication, the pre-replication levels are restored. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1 reassociation with heterochromatin during mitotic exit is required to set up a chromatin permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1a and HP1b and is required for the increased tri-methylation of H3K9 that takes place during G1. RIF1 is also indispensable for recruiting PP1a to heterochromatin, and the interaction between RIF1 and PP1a is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinases at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. We suggest that this is a further mechanism to increase the window of time available pre-replication for SUV39H1/2 to complete the restoration of H3K9me3 levels.

ORGANISM(S): Mus musculus

PROVIDER: GSE299608 | GEO | 2026/09/08

REPOSITORIES: GEO

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RIF1 orchestrates a multi-step restoration of post-replicative H3K9me3

Project description:DNA replication causes the dilution of parental histones along with their specific post-translational modifications. The kinetics of restoring these marks on newly incorporated histones dictate how quickly genomic domains regain their epigenetic identity after replication. H3K9me3 is restored extremely slowly; the process of reconstitution, to achieve the pre-replication levels, continues throughout the following G1. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1’s reassociation with heterochromatin during mitotic exit is required to set up a chromatin environment permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1α and HP1β and is required for the increased tri-methylation of H3K9 that occurs during G1. RIF1 is also indispensable for recruiting Protein Phosphatase 1 (PP1α) to heterochromatin, and the interaction between RIF1 and PP1α is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinase at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. This creates a time- window permissive for SUV39Hs to initiate the reinstatement of H3K9me3.

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RIF1 orchestrates a multi-step restoration of post-replicative H3K9me3

Project description:DNA replication causes the dilution of parental histones along with their specific post-translational modifications. The kinetics of restoring these marks on newly incorporated histones dictate how quickly genomic domains regain their epigenetic identity after replication. H3K9me3 is restored extremely slowly; the process of reconstitution, to achieve the pre-replication levels, continues throughout the following G1 phase. The molecular mechanisms behind this slow reconstitution are unknown. We show here that RIF1′s reassociation with heterochromatin during mitotic exit is required to set up a chromatin environment permissive for histone methyltransferases to resume H3K9me3 deposition. RIF1 facilitates the recruitment of SUV39H1, HP1α and HP1β and is required for the increased tri-methylation of H3K9 that occurs during G1 PHASE. RIF1 is also indispensable for recruiting Protein Phosphatase 1α (PP1α) to heterochromatin, and the interaction between RIF1 and PP1α is essential for the maintenance of H3K9me3 levels. In addition, RIF1-PP1 complex temporally restrains the activity of Aurora kinase at heterochromatin, ensuring that phosphorylation of H3S10 does not precede replication. This creates a time-window permissive for SUV39Hs to initiate the reinstatement of H3K9me3.

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