REVIEWS ocHR。 MATIN DYNAMICS Epigenetic inheritance during the cell cycle Aline V Probst*, Elaine dunleavy*and Genevieve Almouzni 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 The definition of epigenetics has received much atten- Recent research has highlighted DNA methylation tion, as attested by the number of recent publications-. as a bona fide epigenetic mark, and chromatin organiz 942to When originally coined by Waddington in 1942, the ation has emerged as a source of major candidates fo escribe how genes of a term epigenetics defined the causal mechanisms by carriers of information superimposed on that encoded genotype bring about a phenotype. Current definitions which the genes of a genotype bring about a phenotype. by DNA itself (BOX 1). In line with genetic information of epigenetics include the On revisiting this definition in 1987, Holliday applied epigenetic marks must be heritable to qualify as study of heritable changes in the term epigenetic to situations in which changes in true epigenetic information. Furthermore, in contrast to ne function that occur DNA methylation result in changes in gene activity. genetic information, which is meant to be highly stable, without aiteranons to the DnA Today, the most widely accepted definition -which epigenetic information reveals a certain level of plastic we adopt in this Review - designates epigenetics as ity and is inherently reversible. Therefore, one needs Centromere the study of heritable changes in genome function that to understand how a particular chromatin state that is A region of a chromosome that occur without alterations to the DNA sequence. This associated with a particular cell type can survive through is defined by the presence of a definition implies that particular states that define cell multiple cell divisions and, more specifically, how it can naot cresgeand histone hs identity are attained by heritable instructions -the face the dramatic perturbation that occurs during the functions as a platform for epigenetic marks that determine whether, when and passage of the replication fork in S phase. Depending kinetochore assembly during how particular genetic information will be read. The on the nature of the epigenetic mark, different strategies Itoss initial setting up of these epigenetic marks represents to restore or maintain epigenetic states operate, either an establishment phase. Here, we discuss epigenetic immediately following the disruptive event(that is, in a inheritance as the means to ensure the transmission replication-coupled manner)or in a manner that can be of epigenetic marks, once they are established, from separated in time from the disruptive event. mother to daughter cell and potentially from gener- The centromere is an attractive model to discuss the ation to generation. Therefore, epigenetic information concept of epigenetic inheritance during the cell cycle provides a form of memory that is necessary for the (BOX 2). It presents a paradigm for an epigeneticall maintenance of genome function, including both defined locus, because its functionality is not ensured the differential gene expression patter f a given cell by the underlying DNA sequence but rather by its lasticity. UMR21B Centre lineage(encompassing, for example, the maintenance of particular chromatin organization.Once established a cell identity after differentiation, position-effect varie- centromere organization and function have to be stably 6. rue d'Ulm,75231 Paris gation in Drosophila melanogaster, dosage compensa- maintained through multiple cell divisions to ensure tion and imprinting in mammals)and the propagation proper chromosome segregation. Given the essential These authors contributed of essential architectural features, such as telomeres and role of centromeres, the proper inheritance of epigenetic centromeres, that are required for cell viability or pro- marks, including the higher-order organization, which mail: almouzni@curie. fr liferation status. Any unscheduled compromise at these define centromeres, must endure chromatin disruption levels might lead to disease. during the passage of the replication fork or the repair 22009 Macmillan Publishers Limited All rights reservedThe definition of epigenetics has received much atten￾tion, as attested by the number of recent publications1–6. When originally coined by Waddington in 1942, the term epigenetics defined the causal mechanisms by which the genes of a genotype bring about a phenotype7 . On revisiting this definition in 1987, Holliday applied the term epigenetic to situations in which changes in DNA methylation result in changes in gene activity8 . Today, the most widely accepted definition — which we adopt in this Review — designates epigenetics as the study of heritable changes in genome function that occur without alterations to the DNA sequence1 . This definition implies that particular states that define cell identity are attained by heritable instructions — the epigenetic marks that determine whether, when and how particular genetic information will be read. The initial setting up of these epigenetic marks represents an establishment phase. Here, we discuss epigenetic inheritance as the means to ensure the transmission of epigenetic marks, once they are established, from mother to daughter cell and potentially from gener￾ation to generation. Therefore, epigenetic information provides a form of memory that is necessary for the maintenance of genome function, including both the differential gene expression patterns of a given cell lineage (encompassing, for example, the maintenance of a cell identity after differentiation, position­effect varie￾gation in Drosophila melanogaster, dosage compensa￾tion and imprinting in mammals) and the propagation of essential architectural features, such as telomeres and centromeres, that are required for cell viability or pro￾liferation status. Any unscheduled compromise at these levels might lead to disease. Recent research has highlighted DNA methylation as a bona fide epigenetic mark, and chromatin organiz￾ation has emerged as a source of major candidates for carriers of information superimposed on that encoded by DNA itself (BOX 1). In line with genetic information, epigenetic marks must be heritable to qualify as true epigenetic information. Furthermore, in contrast to genetic information, which is meant to be highly stable, epigenetic information reveals a certain level of plastic￾ity and is inherently reversible. Therefore, one needs to understand how a particular chromatin state that is associated with a particular cell type can survive through multiple cell divisions and, more specifically, how it can face the dramatic perturbation that occurs during the passage of the replication fork in S phase. Depending on the nature of the epigenetic mark, different strategies to restore or maintain epigenetic states operate, either immediately following the disruptive event (that is, in a replication­coupled manner) or in a manner that can be separated in time from the disruptive event. The centromere is an attractive model to discuss the concept of epigenetic inheritance during the cell cycle (BOX 2). It presents a paradigm for an epigenetically defined locus, because its functionality is not ensured by the underlying DNA sequence but rather by its particular chromatin organization9 . Once established, centromere organization and function have to be stably maintained through multiple cell divisions to ensure proper chromosome segregation. Given the essential role of centromeres, the proper inheritance of epigenetic marks, including the higher­order organization, which define centromeres, must endure chromatin disruption during the passage of the replication fork or the repair Laboratory of Nuclear Dynamics and Genome Plasticity, UMR218 Centre National de la Recherche Scientifique/Institut Curie, 26, rue d’Ulm, 75231 Paris Cedex 05, France. *These authors contributed equally to this work. Correspondence to G.A. e‑mail: almouzni@curie.fr doi:10.1038/nrm2640 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. Epigenetic inheritance during the cell cycle Aline V. Probst*, Elaine Dunleavy* and Geneviève Almouzni 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. Chromatin DynamiCs REVIEWS 192 | mARcH 2009 | VOlume 10 www.nature.com/reviews/molcellbio © 2009 Macmillan Publishers Limited. All rights reserved