Symmetric inheritance of parental histones governs epigenome maintenance and stem cell identity [scRNA-seq]

Modified parental histones are segregated symmetrically to daughter DNA strands during replication and inherited through mitosis. How this may sustain the epigenome and cell identity remains unknown. Here, we show that transmission of histone-based information during replication maintains epigenome fidelity and embryonic stem cell plasticity. Asymmetric segregation of parental histones H3-H4 in MCM2-2A mutants compromised mitotic inheritance of histone modifications and globally altered the epigenome. This included widespread spurious deposition of repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused de-repression and H3K27me3 redistribution across bivalent promoters correlated with misexpression of developmental genes. MCM2-2A mutation challenged dynamic transitions in cellular states across the cell cycle, enhancing naïve pluripotency and reducing lineage priming in G1. Further, developmental competence was diminished, correlating with impaired exit from pluripotency. Collectively, this argues that epigenetic inheritance of histone modifications maintains a correctly balanced and dynamic chromatin landscape able to support mammalian differentiation. Multiplexed scRNAseq study of WT, MCM2-2A (2 biological replicates, 2 technical replicates) mutant in histone recycling and rescued cell line (MCM2-R, 1 biological replicate) by reversing the mutation back to the WT genotype by genome editing. Additional sample information can be found in Supplementary Table 1.