Key Points
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Centromeric chromatin is the foundation of the kinetochore, and centromere maintenance and kinetochore establishment are tightly coupled to the cell cycle. This is regulated by a complex network of players, including histone variants, histone chaperones, chromatin-remodelling factors and chromatin-modifying enzymes.
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The centric region of centromeres is embedded in pericentric heterochromatin, and both domains are in continuous crosstalk, enabling the formation of a complex higher-order chromatin structure.
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Centromeric chromatin is nucleated by nucleosomes containing the H3 variant CenH3CENP-A, to which the other core components centromere protein B (CENP-B) and CENP-C bind directly (proteins that are conserved in most eukaryotic species). Although centromeres usually form at special tandem repeat DNA sequences, their position is determined epigenetically by CenH3CENP-A.
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Centromeric chromatin consists of CenH3CENP-A nucleosomes interspersed with H3.1 and H3.3 nucleosomes, forming a unique biochemical environment that changes during the cell cycle and is tightly regulated.
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Chromosomes in species with regional centromeres (including humans and a large portion of eukaryotes) can only have one functional centromere. Neocentromeres can form in cases in which this equilibrium is disturbed or in which centromeres are lost.
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Neocentromere formation has been linked to or is concomitant with some disease states, and it is prevalent in chromosome rearrangements in cancer.
Abstract
Centromeric chromatin undergoes major changes in composition and architecture during each cell cycle. These changes in specialized chromatin facilitate kinetochore formation in mitosis to ensure proper chromosome segregation. Thus, proper orchestration of centromeric chromatin dynamics during interphase, including replication in S phase, is crucial. We provide the current view concerning the centromeric architecture associated with satellite repeat sequences in mammals and its dynamics during the cell cycle. We summarize the contributions of deposited histone variants and their chaperones, other centromeric components — including proteins and their post-translational modifications, and RNAs — and we link the expression and deposition timing of each component during the cell cycle. Because neocentromeres occur at ectopic sites, we highlight how cell cycle processes can go wrong, leading to neocentromere formation and potentially disease.
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Acknowledgements
We thank I. A. Drinnenberg, D. Ray-Gallet, D. Filipescu and D. Fachinetti for useful discussion and proofreading of this Review. We also thank H. Tachiwana for drawing the nucleosomal structure illustrations. S.M. thanks the R. Rodriguez laboratory for support. This work was supported by la Ligue Nationale contre le Cancer (Equipe labellisée Ligue), the European Commission Network of Excellence EpiGeneSys (HEALTH-F4-2010-257082), the European Research Council (advanced grant 2009-AdG_20090506 'Eccentric'), the European Commission (large-scale integrating project FP7_HEALTH-2010-259743 'MODHEP'), the French National Research Agency (ANR) ('ChromaTin' ANR-10-BLAN-1326-03, ANR-11-LABX-0044_DEEP and ANR-10-IDEX-0001-02 PSL; and 'CHAPINHIB' ANR-12-BSV5-0022-02) and the Aviesan Instituts thématiques multi-organismes (Aviesan-ITMO) cancer project 'Epigenomics of breast cancer'. S.M. was also supported by the Marie Curie Initial Training Network (Nucleosome 4D), and La Fondation pour la recherche médicale.
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Glossary
- α-Satellite sequences
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Tandem repeat DNA sequences found at centromeres. The sequences are highly divergent among species.
- Neocentromeres
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Ectopic centromeres that are formed at loci other than the usual α-satellite sequence.
- Homotypic
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A nucleosome that has copies of the same variant of H3, H2A or H2B.
- Recycled
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Histones are evicted during S phase and transcription, and new histones can be deposited de novo or the old histones can be deposited again, meaning that they are recycled.
- Heterotypic
-
A nucleosome that has different variants of H3, H2A or H2B.
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Müller, S., Almouzni, G. Chromatin dynamics during the cell cycle at centromeres. Nat Rev Genet 18, 192–208 (2017). https://doi.org/10.1038/nrg.2016.157
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DOI: https://doi.org/10.1038/nrg.2016.157
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