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Chromatin replication and epigenome maintenance

Nature Reviews Molecular Cell Biology volume 13, pages 153–167 (2012)Cite this article

Subjects

Key Points

  • During cell division, DNA sequence along with its distinct organization in chromatin must be transmitted to daughter cells in order to maintain genome stability and keep the memory of established transcriptional states that are central to cell fate and identity.

  • Local chromatin structure and three-dimensional chromosomal organization influence where and when DNA replication initiates. The mechanisms that control replication timing are still enigmatic, but there are strong correlations to developmental decisions as well as the spectra of genome rearrangements observed in cancer.

  • In every S phase, chromatin undergoes disruption as replication forks travel through the genome and sophisticated mechanisms operate in concert with the replisome to reproduce chromatin organization on the new daughter strands. In recent years, many of these mechanisms have been discovered, but how these activities are directed to specific types of chromatin remains a key question.

  • How specific chromatin marks are restored on newly replicated chromatin is seminal to understanding epigenetic inheritance of transcriptional states. Specific self-perpetuating mechanisms have been identified for individual marks, and insights into restoration kinetics have revealed unexpected fluctuation of methylation states through the cell cycle.

  • Cancer development is characterized by genetic and epigenetic alterations. Emerging evidence suggests that replication stress, a known source of genome instability, may also fuel epigenome aberrations and challenge chromatin maintenance.

Abstract

Stability and function of eukaryotic genomes are closely linked to chromatin structure and organization. During cell division the entire genome must be accurately replicated and the chromatin landscape reproduced on new DNA. Chromatin and nuclear structure influence where and when DNA replication initiates, whereas the replication process itself disrupts chromatin and challenges established patterns of genome regulation. Specialized replication-coupled mechanisms assemble new DNA into chromatin, but epigenome maintenance is a continuous process taking place throughout the cell cycle. If DNA synthesis is perturbed, cells can suffer loss of both genome and epigenome integrity with severe consequences for the organism.

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Figure 1: Replication initiation and genome organization.
Figure 2: Chromatin disassembly during replication.
Figure 3: Replication-coupled assembly and maturation of chromatin.
Figure 4: Oscillation of histone H3K27 methylation during the cell cycle.
Figure 5: A vicious circle of (epi)genome instability may add to tumour heterogeneity.

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Acknowledgements

We apologize to those whose publications we were unable to cite owing to space limitations. We would like to thank Z. Jasencakova and R. Pocock for critical reading of this manuscript, and our anonymous reviewers, I. Kamalyukova, C. B. Stromme and R. Martienssen for useful comments. C.A. is supported by a Human Frontiers Scientific Program long-term fellowship and the Danish Medical Research council (FSS). The A.G. laboratory is supported by a European Research Council Starting Grant (ERC2011StG, no. 281,765), the Lundbeck Foundation, the Danish Cancer Society, the Novo Nordisk Foundation, the Danish Medical Research Council and European Commission ITN FP7-PEOPLE2008 'Nucleosome4D'.

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    Constance Alabert & Anja Groth

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Glossary

Epigenetics

The studies of heritable changes in genome function that occur without a change in DNA sequence.

Replication stress

General term referring to deregulation of replication. This can include fork problems (change of speed, stalling or collapse) and replication initiation defects.

Epigenome

The epigenome refers to the overall epigenetic state of a cell, including histone and DNA marks, histone variants, nucleosome positioning and higher-order structures.

Chromosomal architecture

Three-dimensional organization of chromosomes in the nucleus. For example, each chromosome occupies a territory in the nucleus and will take up a specific higher-order structure of open and compact domains that is partly cell type specific.

Nucleosome assembly

A stepwise process starting with the deposition of two H3–H4 dimers or potentially a (H3–H4)2 tetramer onto DNA to form a tetrasome. This is followed by the incorporation of two H2A–H2B dimers to form a nucleosome core particle.

Histone variants

Replacement histones differ in amino acid sequence from canonical S phase histones to varying extents. They are often incorporated by dedicated pathways to serve specialized functions.

Replication origins

Sites in the genome where replication initiates, giving rise to two forks that progress away from the origin in opposite directions.

Nucleosome-free regions

(NFRs). Sites of reduced nucleosome occupancy compared with the immediate surrounding regions. NFRs display sensitivity to DNase I, which is likely to result from high histone exchange or DNA structures that resist nucleosome formation.

Origin decision point

(ODP). Transition point in late G1phase that specifies the origins that will fire in the following S phase. It probably represents a change at specific pre-replication complexes (pre-RCs), which potentiates some pre-RCs while preventing others from initiating.

Replicons

Stretches of DNA replicated from a single origin.

DNA halo assay

An approach to visualize DNA loops in interphase nuclei. Nuclei are permeabilized and depleted of histone and soluble proteins on slides, allowing unwinding of supercoiled DNA loops to form a halo around an insoluble scaffold.

Cohesin complex

Ring-shaped multi-protein complex (composed of SMC1, SMC3, RAD21 and sister-chromatid cohesion protein 3 (SCC3)) that by embracing chromatin fibres mediates sister chromatid cohesion and has roles in DNA repair and transcription.

DNA superhelicity

Positive or negative supercoiling of DNA molecules.

SILAC

'Stable isotope labelling with amino acids in cell culture' is an approach for in vivo metabolic labelling of proteins with amino acids containing light or heavy isotopes and is used for quantitative mass spectrometry.

Histone chaperone

Factor that associates with histones and stimulates a reaction involving histone transfer without being part of the final product.

Sister chromatid cohesion

The joining of two sister chromatids upon chromosome replication that enables proper chromosome segregation.

Okazaki fragment maturation

Okazaki fragments are short DNA molecules of approximately 100 to 200 nucleotides in eukaryotes. They are initiated by primase–Pol α (DNA polymerase α) on lagging strands by the synthesis of an RNA primer with a short DNA extension, which is then further extended by Pol δ. The primer and part of the DNA is removed as two Okazaki fragments are ligated together.

Nucleosome dyads

Axes of symmetry in the nucleosome.

iPOND

'Isolation of proteins on nascent DNA' is a technology to isolate proteins on newly synthesized DNA by combining EdU labelling with Click-iT chemistry.

RNA interference

(RNAi). Processing of transcripts into small double-stranded RNAs that can silence gene expression. Small RNAs can work by interfering with translation to induce post-transcriptional gene silencing or induce chromatin-dependent gene silencing by interacting with nascent transcripts and targeting chromatin-modifying complexes.

Senescence

A state of irreversible cell cycle arrest that occurs as a consequence of continued cell division in primary mammalian cells in part owing to erosion of telomeres. Senescence contributes to organismal ageing and at the same time provides a barrier to carcinogenesis.

Replicative ageing

Accumulation of genetic and epigenetic defects at each round of replication during life span in yeast.

G-quadruplex structures

(G4 structures). Guanine-rich DNA sequences capable of forming four-stranded secondary structures by square arrangement of guanines.

Chromatin remodeller

A large multi-protein machine that, through ATP hydrolysis, enables access to nucleosomal DNA by altering the structure, composition and/or position of nucleosomes.

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Alabert, C., Groth, A. Chromatin replication and epigenome maintenance. Nat Rev Mol Cell Biol 13, 153–167 (2012). https://doi.org/10.1038/nrm3288

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