Recycling of Histones H2A-H2B provides short-term memory of chromatin states [SCAR-seq II]

Chromatin landscapes are disrupted during DNA replication and need to be restored faithfully to maintain appropriate gene expression, including post-translational modifications (PTMs) of newly deposited histones. Whether histones H2A-H2B are accurately recycled during DNA replication and the behaviour of their associated marks during and post replication is unknown. Here we comprehensively map key modifications on H2A-H2B including H2A.Z during DNA replication. We show that H2AK119ub, H2BK120ub, and H2A.Z are recycled quantitatively and accurately during DNA replication in a symmetrical manner. Recycling occurs independently from H3-H4 chaperone pathways apart from a minor role for Polymerase alpha. H2A-H2B modifications are restored rapidly post replication and are important for timely and accurate restoration of H3-H4 marks, such as H3K27me3. This work uncovers H3-H4 and H2A-H2B crosstalk in epigenome propagation across DNA replication and suggests a model where rapid short-term memory of recycled H2A-H2B marks facilitates reestablishment of slow, long-term memory chromatin states. Overall design: SCAR-seq (Sister Chromatids After Replication) time-series measuring histone partition of H3K27me3, or H4K20me0 in wildtype (WT), MCM2 histone-binding mutant (MCM2-2A), or Pole4 KO mouse embryonic stem cells (Parental WT cells, 2 MCM2-2A clones, 2 Pole4KO clones, >2 replicates per cell line, stranded input controls). Note that the strandedInputs for Pole4KO cells are available in the accompanying Subseries SCAR-seq (GSE204984; GSM6203641-6).