Cell Figure 3. A Model of the Inheritance of chromatin States Different nucleosome states hromatin states have been proposed to carry writable epigenetic information. Shown in Initiation of replication histone isoforms). After passage of the replica- tion fork, nucleosomes apparently segregate andomly to the two daughter chromosomes. oon thereafter, newly synthesized nucleo- omes (gray) are assembled onto the chromo- omes. in order for chromatin states to be her corporation of ne able for more than a handful of generations, synthesized nucleo w nucleosomes must be modified to the ame state as surrounding maternal nucleo- one possible model the proteins that associate with maternal nucle- somes locally instruct (arrows)new nucleo- ome feedback mechanism by which old Modification of new nucleosome telomeric regions contain multiple gene families, including ure 3). A similar p non occurs in the malaria patho- the cell-surface FLo genes, the thiamine-biosynthesis TH/ gen Plasmodium falciparum, where virulence factors such genes, and the hexose kinase HXK genes. Genes located as the erythrocyte-adhesion molecule PfEMP1 are er near telomeres are subject to variegated silencing; for coded subtelomerically and vary in expression from on example, a reporter gene adjacent to an artificially con- to off approximately every 50 generations(Roberts et al. structed telomere was shown to switch from on to off ap- 1992) in a Sir2-dependent manner. Stochastic subtelo- proximately every 10 to 15 generations( Gottschling et al meric switching of cell-surface genes of pathogens may 1990). Two related histone deacetylation mechanisms are help evade the host immune system, and presumably esponsible for subtelomeric silencing: genes immediately switching rates are tuned so that the time of exposure of proximal to the telomeres are silenced by the silent infor- an antigen is shorter than the time required for an effective mation-regulator Sir) complex, whereas genes located immune response somewhat more distant are silenced by Hda1 ( Gottschling Prions(proteins that can heritably occur in more than et aL., 1990; Halme et aL., 2004). Although the linkage be- one conformation) are fascinating examples of epige tween histone deacetylation and silencing is well estab- netic information carriers that are stable for relatively shed the mechanism of inheritance of chromatin states ng timescales. Prion proteins were originally described (both on and off) is still an active area of investigation(Fig- as infectious protein conformations that convert the ce128,655668. February23,2007@2007 Elsevier Inc.659telomeric regions contain multiple gene families, including the cell-surface FLO genes, the thiamine-biosynthesis THI genes, and the hexose kinase HXK genes. Genes located near telomeres are subject to variegated silencing; for example, a reporter gene adjacent to an artificially con￾structed telomere was shown to switch from on to off ap￾proximately every 10 to 15 generations (Gottschling et al., 1990). Two related histone deacetylation mechanisms are responsible for subtelomeric silencing: genes immediately proximal to the telomeres are silenced by the silent infor￾mation-regulator (Sir) complex, whereas genes located somewhat more distant are silenced by Hda1 (Gottschling et al., 1990; Halme et al., 2004). Although the linkage be￾tween histone deacetylation and silencing is well estab￾lished, the mechanism of inheritance of chromatin states (both on and off) is still an active area of investigation (Fig￾ure 3). A similar phenomenon occurs in the malaria patho￾gen Plasmodium falciparum, where virulence factors such as the erythrocyte-adhesion molecule PfEMP1 are en￾coded subtelomerically and vary in expression from on to off approximately every 50 generations (Roberts et al., 1992) in a Sir2-dependent manner. Stochastic subtelo￾meric switching of cell-surface genes of pathogens may help evade the host immune system, and presumably switching rates are tuned so that the time of exposure of an antigen is shorter than the time required for an effective immune response. Prions (proteins that can heritably occur in more than one conformation) are fascinating examples of epige￾netic information carriers that are stable for relatively long timescales. Prion proteins were originally described as infectious protein conformations that convert the Figure 3. A Model of the Inheritance of Chromatin States Chromatin states have been proposed to carry heritable epigenetic information. Shown in green and white are two different nucleosome states (possibly carrying distinct covalent mod￾ification patterns or distinct subsets of variant histone isoforms). After passage of the replica￾tion fork, nucleosomes apparently segregate randomly to the two daughter chromosomes. Soon thereafter, newly synthesized nucleo￾somes (gray) are assembled onto the chromo￾somes. In order for chromatin states to be her￾itable for more than a handful of generations, new nucleosomes must be modified to the same state as surrounding maternal nucleo￾somes. In one possible model of this feedback the proteins that associate with maternal nucle￾osomes locally instruct (arrows) new nucleo￾somes to carry the appropriate modification/ variant pattern. This model is one of several proposed, but all models have in common some feedback mechanism by which old nucleosomes influence the states of the newly synthesized nucleosomes deposited at a given locus. Cell 128, 655–668, February 23, 2007 ª2007 Elsevier Inc. 659