REVIEWS Box 1 Candidate players for epigenetic inheritance transmission of information beyond the DNA sequence during cell division and from positon of epigenetic information is crucial for Nude maintaining differential gene expression chromatin patterns in differentiation, development and disease. Candidates for key players in different levels of chromatin include dna non-histone chromatin proteins that bind nuclear RNA and higher-order organization, as well as positional information. We need to distinguish between marks that reflect Nucleosome heat shock or damage)and those that are long-term instructions. These long-ter instructions might be inherited independently of the initial trigger, might qualify as epigenetic marks and could contribute to cellular memory2?. DNA wraps around a histone octamer that is 3 Histone modifications composed of one(H3-H4), tetramer capped by two H2A-H2B dimers. Together with the linker histone h1. this forms the nucleosome the basic building block of chromatin(see the figure). DNA itself is covalently modified by methylation of cytosine residues. Histones are also post-translationally modified (for example, by methylation(Me), acetylation (Ac)and phosphorylation (P)), and each mark constitutes a signal that is read alone or in combination with other modifications on the same or neighbouring histones as a histone code. Families of methyl-or histone-binding proteins decipher the regulatory information that is encoded by DNA methylation and histone marks. The presence of histone variants adds further complexity. Whereas the replicative variant H3.1 is DNA incorporated in a DNA synthesis-dependent manner, replacement variants, such as H3. 3 and the Histone variants specific histone H3 variant CenH3, are incorporated in a DNA synthesis-independent manner and result in nucleosomes with atypical stability. Nucleosomal chains fold into higher-order chromatin structures that are potentially organized with non-coding RNA components. The position of a particular chromosomal domain in the nucleus constitutes an additional level of instructions for gene expression. of damaged DNA. The basic rules that can be learnt variants that is either coupled or not coupled to DNA from the maintenance of a well-defined domain, such as replication. We discuss the maintenance of hetero the centromere, might further our understanding of the chromatin using the example of centromeres and show, general principles that underlie the inheritance of by means of reprogramming events that occur during epigenetic states. development, the reversibility of epigenetic marks and The actual nature and diversity of histone modifi- their dynamic Heterochromatin cations and modifiers, and histone variants, have A chromatin regon that been covered elsewhere, as have the challenges posed Inheritance at the replication fork remans oneens td an roughout to chromatin during replication and repair 21. Here, we In each cell cycle, the integrity of genetic and epigenetic characterized by a specific discuss the sophisticated mechanisms that have evolved information is challenged during DNA replication in order to facilitate the inheritance of epigenetic marks When DNA replicates, chromatin undergoes a wave of not only at the replication fork, but also at other stages disruption and subsequent restoration in the wake of the cell cycle. This Review provides an overview of of the passage of the replication fork. Whereas lineage tic state, resulting in an our current knowledge concerning the inheritance preservation requires the faithful maintenance of epi Tered cellular identity of DNA methylation, histone modifications and histone genetic marks, DNA replication also presents a window NATURE REVIEWS MOLECULAR CELL BIOLOGY 22009 Macmillan Publishers Limited All rights reservedNature Reviews | Molecular Cell Biology Nucleosome Structural RNA Higher-order chromatin Nuclear position Nucleus P DNA methylation DNA Histone modifications Histone variants Me Ac Ac Chromatin-binding protein 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. of damaged DNA. The basic rules that can be learnt from the maintenance of a well­defined domain, such as the centromere, might further our understanding of the general principles that underlie the inheritance of epigenetic states. The actual nature and diversity of histone modifi￾cations and modifiers10, and histone variants11, have been covered elsewhere, as have the challenges posed to chromatin during replication and repair12,13. Here, we discuss the sophisticated mechanisms that have evolved in order to facilitate the inheritance of epigenetic marks not only at the replication fork, but also at other stages of the cell cycle. This Review provides an overview of our current knowledge concerning the inheritance of DNA methylation, histone modifications and histone variants that is either coupled or not coupled to DNA replication. We discuss the maintenance of hetero￾chromatin using the example of centromeres and show, by means of reprogramming events that occur during development, the reversibility of epigenetic marks and their dynamics. inheritance at the replication fork In each cell cycle, the integrity of genetic and epigenetic information is challenged during DNA replication. When DNA replicates, chromatin undergoes a wave of disruption and subsequent restoration in the wake of the passage of the replication fork. Whereas lineage preservation requires the faithful maintenance of epi￾genetic marks, DNA replication also presents a window Box 1 | Candidate players for epigenetic inheritance Epigenetic inheritance refers to the transmission of information beyond the DNA sequence during cell division and from one generation to the next1,3. Inheritance of epigenetic information is crucial for maintaining differential gene expression patterns in differentiation, development and disease. Candidates for key players in epigenetic inheritance that are situated of different levels of chromatin include DNA and histone modifications, histone variants, non-histone chromatin proteins that bind directly to DNA or to histone modifications, nuclear RNA and higher-order organization, as well as positional information. We need to distinguish between marks that reflect short-term instructions and can quickly revert in response to a signal (for example, heat shock or damage) and those that are long-term instructions. These long-term instructions might be inherited independently of the initial trigger, might qualify as epigenetic marks and could contribute to cellular memory2 . DNA wraps around a histone octamer that is composed of one (H3–H4)2 tetramer capped by two H2A–H2B dimers. Together with the linker histone H1, this forms the nucleosome — the basic building block of chromatin (see the figure). DNA itself is covalently modified by methylation of cytosine residues. Histones are also post-translationally modified (for example, by methylation (Me), acetylation (Ac) and phosphorylation (P)), and each mark constitutes a signal that is read alone or in combination with other modifications on the same or neighbouring histones as a ‘histone code’. Families of methyl- or histone-binding proteins decipher the regulatory information that is encoded by DNA methylation and histone marks. The presence of histone variants adds further complexity. Whereas the replicative variant H3.1 is incorporated in a DNA synthesis-dependent manner, replacement variants, such as H3.3 and the centromere￾specific histone H3 variant CenH3, are incorporated in a DNA synthesis-independent manner and result in nucleosomes with atypical stability. Nucleosomal chains fold into higher-order chromatin structures that are potentially organized with non-coding RNA components. The position of a particular chromosomal domain in the nucleus constitutes an additional level of instructions for gene expression. REVIEWS NATuRe ReVIeWS | Molecular cell Biology VOlume 10 | mARcH 2009 | 193 © 2009 Macmillan Publishers Limited. All rights reserved