Abstract
Proper determination of cell fates depends on epigenetic information that is used to preserve memory of decisions made earlier in development. Post-translational modification of histone residues is thought to be a central means by which epigenetic information is propagated. In particular, modifications of histone H3 lysine 27 (H3K27) are strongly correlated with both gene activation and gene repression. H3K27 acetylation is found at sites of active transcription, whereas H3K27 methylation is found at loci silenced by Polycomb group proteins. The histones bearing these modifications are encoded by the replication-dependent H3 genes as well as the replication-independent H3.3 genes. Owing to differential rates of nucleosome turnover, H3K27 acetylation is enriched on replication-independent H3.3 histones at active gene loci, and H3K27 methylation is enriched on replication-dependent H3 histones across silenced gene loci. Previously, we found that modification of replication-dependent H3K27 is required for Polycomb target gene silencing, but it is not required for gene activation. However, the contribution of replication-independent H3.3K27 to these functions is unknown. Here, we used CRISPR/Cas9 to mutate the endogenous replication-independent H3.3K27 to a non-modifiable residue. Surprisingly, we find that H3.3K27 is also required for Polycomb target gene silencing despite the association of H3.3 with active transcription. However, the requirement for H3.3K27 comes at a later stage of development than that found for replication-dependent H3K27, suggesting a greater reliance on replication-independent H3.3K27 in post-mitotic cells. Notably, we find no evidence of global transcriptional defects in H3.3K27 mutants, despite the strong correlation between H3.3K27 acetylation and active transcription.
Highlights
Inside the nucleus, DNA is wrapped around histone proteins to form nucleosomes, the basic building block of chromatin
Identifying which histone modifications are required for gene regulation, and defining the mechanisms through which they function in the maintenance of cell identity, remains a longstanding research challenge
Modifications of H3K27 are associated with both gene activation and gene silencing (i.e. H3K27 acetylation and methylation, respectively)
Summary
DNA is wrapped around histone proteins to form nucleosomes, the basic building block of chromatin. In addition to compacting the genome within the confines of a small nuclear space, histone proteins serve as substrates for regulating genome activity. Many DNA-dependent processes are regulated by histone post-translational modifications (PTMs). Histone PTMs function primarily by controlling the assembly of regulatory complexes at specific loci in the genome, either through direct alteration of chromatin structure, or by serving as binding sites for trans-acting factors [1]. Due to the inheritance of parental histones by daughter cells during cell division, histone PTMs have the potential to propagate epigenetic information over time, thereby helping to maintain the gene expression programs underlying cell identity. A longstanding objective has been to identify histone PTMs involved in gene regulation and to determine their relative importance in maintenance of cell identity
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