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Parental nucleosome segregation and the inheritance of cellular identity

Abstract

Gene expression programmes conferring cellular identity are achieved through the organization of chromatin structures that either facilitate or impede transcription. Among the key determinants of chromatin organization are the histone modifications that correlate with a given transcriptional status and chromatin state. Until recently, the details for the segregation of nucleosomes on DNA replication and their implications in re-establishing heritable chromatin domains remained unclear. Here, we review recent findings detailing the local segregation of parental nucleosomes and highlight important advances as to how histone methyltransferases associated with the establishment of repressive chromatin domains facilitate epigenetic inheritance.

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Fig. 1: Histone dynamics at the eukaryotic replisome.
Fig. 2: Applications used for determining the fate of parental nucleosomes across DNA replication.
Fig. 3: Proposed mechanisms for the local segregation of parental nucleosomes in facultative late-replicating repressive chromatin.
Fig. 4: Mechanisms for potential to acquire a new cellular identity.

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Acknowledgements

The authors thank L. Vales for discussion and revision of the manuscript. They also thank K. J. Armache for revision of the manuscript. This work was performed during a sabbatical of A.L. in the laboratory of D.R., New York University Langone Health. T.M.E. is supported by US National Cancer Institute NIH grant 3R01CA199652-14S1. A.L. is supported by grants from Comisión Nacional de Investigación Científica y Tecnológica (FONDECYT 1200577 and Programa de Apoyo a Centros con Financiamiento Basal AFB170004) of Chile. D.R. is supported by the Howard Hughes Medical Institute and the National Cancer Institute (NIH 9R01CA199652-13A1 grant).

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T.M.E. and A.L. wrote the manuscript. All authors substantially contributed to the discussion of content and reviewing/editing of the manuscript before submission.

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Correspondence to Danny Reinberg.

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D.R. is a co-founder of Constellation Pharmaceuticals and Fulcrum Therapeutics. The other authors declare no competing interests.

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Glossary

Euchromatin

Light-staining, decondensed, gene-rich and transcriptionally active and accessible regions of the genome, enriched in trimethylated histone H3 lysine 4 (H3K4me3) and acetylated histone H3 (H3ac).

Heterochromatin

Dark-staining, condensed, gene-poor and repetitive regions of the genome. These regions can be further classified into facultative and constitutive heterochromatin that are enriched in trimethylated histone H3 lysine 27 (H3K27me3) and H3K9me3, respectively.

Transcriptional signature

Transcriptional patterns that are specific to a given cell type and are responsible for cellular identity.

Epigenetic mechanism

A molecular process that is involved in establishing a heritable state of chromatin by modifications of DNA or post-translational modification of the histone H3 isoforms, such as DNA methylation or trimethylated histone H3 lysine 27 (H3K27me3)/H3K9me3, respectively.

Parental histones

Histones that have existed before the S phase-specific synthesis of histones.

Epigenetic modification

This term is incorrectly used in many circumstances. The designation refers to DNA methylation and post-translational modifications to histones that facilitate transcriptional programmes that are inherited across cell division. Indeed, as of today in mammals, only two modifications to histone H3 are known to be epigenetic (as described in the glossary definition for ‘epigenetic mechanism’). In yeast, only deacetylation of lysine 16 of histone H4 establishes an epigenetic programme at three specific loci, as explained in the main text.

‘Read–write’ mechanism

Enzymatic activity of some methyltransferases that exhibit a self-contained positive-feedback loop. Thus far, only SUV39H1/SUV39H2 and Polycomb repressive complex 2 (PRC2) have shown this activity, in which a domain of the SUV39H1/SUV39H2 polypeptide or a subunit of PRC2 recognizes the product of its catalysis, trimethylated histone H3 lysine 9 (H3K9me3) or H3K27me3, respectively. These binding events result in the stimulation of the activity of the SET domain, which comprises the same polypeptide in the case of SUV39H1/SUV39H2 or another subunit in the case of PRC2, further spreading the histone modification.

Allosteric stimulation

Activation of an enzyme mediated by a small regulatory molecule that interacts at a site other than the active site.

Newly synthesized ‘naive’ histones

Histones that have been recently synthesized and contain only few post-translational modifications, including monomethylated histone H3 lysine 9 (H3K9me1), acetylated histone H4 lysine 5 (H4K5ac) and H4K12ac.

Parental nucleosome segregation

The disassembly of the parental nucleosomes into one histone (H3–H4)2 tetramer and two histone H2A–H2B dimers ahead of the replication fork and their placement behind the fork to the leading and lagging strand.

Histone eviction

Complete removal of histones forming part of nucleosomes, as a consequence of DNA processing, such as transcription, DNA replication and DNA repair.

Histone turnover

The rate of histone exchange at a particular locus. In the main text, we focus mainly on the histone exchange associated with transcription as chromatin within an active transcriptional domain has higher histone turnover than chromatin within a silent transcriptional domain.

Replication timing

The order in which segments of DNA are duplicated during the S phase of the cell cycle. Correlation exists where early replication timing corresponds to euchromatin and late replication timing corresponds to heterochromatin regions.

Bivalent promoters

Promoters that have both repressive (trimethylated histone H3 lysine 27 (H3K27me3)) and activating (H3K4me3) histone post-translational modifications within the same nucleosome.

Oncohistones

Recurrent mutations in histone genes that lead to the expression of mutant histones with oncogenic characteristics. Their expression affects the global chromatin landscape of the cell.

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Escobar, T.M., Loyola, A. & Reinberg, D. Parental nucleosome segregation and the inheritance of cellular identity. Nat Rev Genet (2021). https://doi.org/10.1038/s41576-020-00312-w

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