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Epigenetic inheritance during the cell cycle

Key Points

  • Epigenetic inheritance concerns the mechanisms that ensure transmission of epigenetic marks from mother to daughter cell. Chromatin modifications and nuclear organization are candidates for epigenetic marks — whether they fulfil the criterion of heritability and what mechanisms ensure their propagation is an area of intensive research.

  • The passage of the replication fork challenges genetic and epigenetic information. Depending on the nature of the epigenetic mark, its inheritance can be ensured in a replication-coupled manner or in a timely manner that is separated from the disruptive event.

  • DNA methylation is inherited at the replication fork in a semi-conservative manner. The redistribution of parental histones, together with their parental modifications at the fork, affects the transmission of information. Histone chaperones have an important role in controlling histone dynamics at the fork. The maintenance of DNA methylation and histone modifications is interconnected at the replication fork.

  • The centromere-specific histone H3 variant CenH3 (CENP-A in humans) is inherited in a replication-uncoupled manner — new CENP-A is deposited in late telophase–G1 phase, highlighting a new window of inheritance during the cell cycle.

  • Restoration of pericentric heterochromatin after passage of the replication fork involves an RNA interference-dependent mechanism in fission yeast, whereas for mammals evidence suggests that the DNA methylation maintenance machinery, chromatin assembly factors and histone modifiers operate in a concerted manner to ensure heterochromatin maintenance.

  • Reprogramming during development highlights the reversibility of epigenetic states.

Abstract

Studies that concern the mechanism of DNA replication have provided a major framework for understanding genetic transmission through multiple cell cycles. Recent work has begun to gain insight into possible means to ensure the stable transmission of information beyond just DNA, and has led to the concept of epigenetic inheritance. Considering chromatin-based information, key candidates have arisen as epigenetic marks, including DNA and histone modifications, histone variants, non-histone chromatin proteins, nuclear RNA as well as higher-order chromatin organization. Understanding the dynamics and stability of these marks through the cell cycle is crucial in maintaining a given chromatin state.

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Figure 1: Asymmetric DNA replication and coupling of inheritance of DNA and histone marks.
Figure 2: Nucleosome dynamics and mixing of parental and new H3–H4 dimers.
Figure 3: Fate of old and new H3–H4 dimers and their marks at the fork.
Figure 4: Inheritance of histone H3 variants outside of S phase.
Figure 5: Maintaining pericentric heterochromatin in fission yeast and mouse.
Figure 6: Reprogramming during development and the fate of epigenetic marks.

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Acknowledgements

We apologize for not quoting all of our colleagues for their contributions owing to space limitations. We thank D. Roche for providing images, J. P. Quivy and P. A. Defossez for critical comments to the manuscript. A.V.P. is supported by a European Molecular Biology Organization (EMBO) long-term fellowship. A.V.P., E.D. and G.A. are supported by La Ligue Nationale contre le Cancer (Equipe Labellisée la Ligue), Programme Incitatif Cooperatif (PIC) programmes 'Retinoblastome' and 'Replication, Instabilite chromosomique et cancer', the European Commission Network of Excellence Epigenome, ACI-2007-Cancéropôle IdF 'Breast cancer and Epigenetics' and the Agence Nationale de la Recherche.

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Glossary

Epigenetics

This term was coined by Waddington in 1942 to describe how genes of a genotype bring about a phenotype. Current definitions of epigenetics include the study of heritable changes in gene function that occur without alterations to the DNA sequence.

Centromere

A region of a chromosome that is defined by the presence of a centromere-specific histone H3 variant (CenH3) and that functions as a platform for kinetochore assembly during mitosis.

Heterochromatin

A chromatin region that remains condensed throughout the cell cycle and that is characterized by a specific chromatin signature.

Reprogramming

The induced reversal of an epigenetic state, resulting in an altered cellular identity.

Histone chaperone

A factor that associates with histones and stimulates a reaction that involves histone transfer without being part of the final product.

DNA methyltransferase

An enzyme that transfers methyl groups from S-adenosylmethionine to specific adenines or cytosines in DNA.

Histone H3 variant

A replicative histone H3 variant is expressed and incorporated during DNA replication (for example, H3.1 and H3.2), whereas a replacement variant is expressed throughout the cell cycle and is incorporated in a DNA-synthesis-independent manner (for example, H3.3 and the centromere-specific histone H3 variant CenH3).

Histone deacetylase

An enzyme that removes acetyl groups from histones.

Lys methyltransferase

An enzyme that catalyses the addition of a methyl group to specific Lys residues in histones and other non-histone proteins.

Lys acetyltransferase

An enzyme that catalyses the addition of an acetyl group to specific Lys residues in histones and other non-histone proteins.

Heterochromatin protein 1

(HP1). A chromodomain-containing protein that binds to methylated K9 on histone H3 and is associated with heterochromatin in fission yeast (Swi6), mammals (HP1) and Drosophila melanogaster (HP1).

Pericentric heterochromatin

A heterochromatic region adjacent to chromatin containing the centromere-specific histone H3 variant CenH3, and which is considered to be typical constitutive heterochromatin.

Small interfering RNA

A short, non-coding RNA (22-nt long) that is processed from longer double-stranded RNA by the RNA interference machinery. Such non-coding RNAs confer target specificity to the silencing complexes in which they reside.

Phospho–methyl switch

The phosphorylation of histone H3S10 during late G2 phase and mitosis interferes with the binding of heterochromatin protein 1 to the adjacent methylated H3K9 residue.

Chromocentre

A cluster of constitutive heterochromatin from different chromosomes that is formed during interphase.

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Probst, A., Dunleavy, E. & Almouzni, G. Epigenetic inheritance during the cell cycle. Nat Rev Mol Cell Biol 10, 192–206 (2009). https://doi.org/10.1038/nrm2640

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