Cell, Vol. 93, 301–303, May 1, 1998, Copyright 1998 by Cell Press

The Mystique of Epigenetics

Benjamin Lewin Cell

Epigenetic effects have often enough been viewed as verging on the mystical. It is a paradox of conventional genetics that two alleles can have the same genetic sequence but show different states of inheritance. This can be resolved by supposing that the ability to inherit a nongenetic state reflects the existence of templating. There must be a transition between two (discontinuous) states (equilibrium situations are excluded). Each of the alternative states is stable. One of these states can be regarded as the naı¨ve state—what is achieved simply by synthesis of the relevant components. The other state can be regarded as a determined state, in which some special property has been conferred that distinguishes the components (or their macromolecular assembly) from the naı¨ve state. In this issue of Cell, we dispel mysticism by considering the molecular bases for a variety of situations involving epigenetic effects. Their causes fall into two general classes, depending on whether DNA or protein is the target for conversion from naı¨ve to determined state. Modification of DNA involves the covalent addition of a group to a specific sequence of DNA. Typically the modification is methylation of cytosine in the dinucleotide CpG (usually this is associated with inactivity of the target sequence). Because the methylated sequence is palindromic, both strands of DNA can be methylated. The modification is inherited epigenetically because of the existence of a system that recognizes hemimethylated sequences (with one strand modified) and converts them to the fully methylated state (with both strands modified). The epigenetic state can be reversed by removing the methyl group. Modification of proteins also can create an epigenetic state. The acetylation of histones in chromatin is analogous to the methylation of DNA (although acetylation is associated with activity, and deacetylation is associated with inactivity). Both are active processes, catalyzed by the appropriate enzymes (histone acetylases and deacetylases). Examples of acetylated sites that appear to be self-propagating are provided by centromeres (Ekwall et al., 1997). How does an acetylated site reproduce itself? One possibility is that the presence of acetylated histones provides a signal for acetylases to act on unmodified histones in the same or adjacent nucleosomes. This would be a close parallel to the system for maintenance of methylation. It would imply a requirement for a deacetylase to reverse the state. Protein templating takes several forms. In the simplest case, a region of chromatin may exist in either of two forms, one that is detected as active, and one that is detected as inactive. (Actually all that is required to maintain an epigenetic condition is that there should be one condition that is functionally different from all other conditions. Typically this is an inactive conformation created by the determined state.) The determined state

Overview

is created by a discrete event, equivalent to nucleation of a particular structure. The state may then be propagated along chromatin from the nucleated center; the variable distance of propagation gives rise to such effects as position effect variegation (in which the probability of inactivation of a gene translocated to a position near heterochromatin decreases with its distance from heterochromatin). One of the characteristics of a state that depends upon an alternative protein structure is that the extent of the affected region is unlikely to have defined limits. Because the determined condition propagates (perhaps analogous to a crystal), its extent may be limited by the (variable) supply of components (unless a discrete boundary is encountered, which is not usually the case). What conditions must be fulfilled to create an epigenetic effect? A discrete event must generate a difference in structure, either by de novo methylation of DNA or by modifying proteins or nucleating a protein structure. The structure must be perpetuated, in the case of methylation because of the existence of an extrinsic enzyme system that acts constitutively on hemimethylated DNA, in the case of a protein structure because the assembly is intrinsically self-templating (with the extrinsic condition of a requirement for constitutive production of the protein components). For the effect to be fully reversible, a demethylase must act upon modified DNA sites (although perpetuation of the methylated site could be blocked by withdrawing the methylase, so that each replication produced one hemimethylated and one unmethylated progeny). A proteinaceous structure could be abolished by failure to provide subunits needed to duplicate it or by a specific (energy-requiring?) modification of the structure. The consequences of epigenetic modification by methylation are seen in states of imprinting, most dramatically when the two parental alleles in an early embryo show a difference in their ability to function (for review see Surani, 1998). When the methylated state is associated with inactivity, survival of the embryo requires the provision of a functional allele from the parent that is nonmethylated. More complex effects may be produced by regulatory circuits, but the crucial common event is determination of the state of methylation of a particular CpG in the germ line. Because switching of imprinting occurs regularly in either direction (each time a paternal allele passes through an oocyte or a maternal allele passes through a sperm), it is clear that both modification and demodification are active processes. In fact, specific sequences are required to reset methylation in either direction. The enzymes responsible for these events (de novo methylase and demethylase) remain to be characterized. The formation of heterochromatin reflects the generation of a structure that imposes inactivity on a region. Its extent can vary from entire chromosomes or other large visible structures to much smaller regions (whose lengths are measured at the molecular rather than chromosomal level) in which gene expression is silenced in yeast. Such a structure is perpetuated through cell division, but its formation is not necessarily an epigenetic

Cell 302

event if it does not have an alternative (active) state. Epigenetic effects are created when the structure spreads into adjacent regions for varying distances, so that in some cells a particular gene is inactivated, while in other cells it remains active; and these effects are perpetuated through division. The nucleation and propagation events have been characterized in terms of molecular components for silencing at yeast telomeres (for review see Grunstein, 1998). More than one type of event may be required to create the heterochromatic state. Accretion of specific protein components is required, and deacetylation also may be necessary for formation of the determined structure. Evidence from position effect variegation in Drosophila suggests that here the effects may not be limited simply to linear spread from an activating center, but there may be competitive effects in which different regions of heterochromatin compete for proteins that are present in limiting amounts (for review see Wakimoto, 1998). Indeed, interchromosomal effects may extend to specific interallelic interactions, as seen in situations such as transvection (activation involving paired homologs) or pairing-dependent repression (for review see Henikoff and Comai, 1998). Epigenetic effects of this nature typically have been characterized by their propagation through mitosis, but can also be perpetuated through meiosis. This implies simply that the necessary conditions (including production of the necessary components) occur in both types of division. It means that the determined structures can be perpetuated through the various structural changes that occur to chromosomes in meiosis. This is relatively straightforward for methylation (see Colot et al., 1996). A peculiarity of some note is the propagation of epigenetic effects through female meiosis in Drosophila (Cavalli and Paro, 1998). Because there is no methylation in Drosophila, this effect must involve a proteinaceous structure. It may be significant that epigenetic transmission occurs only through female meiosis (where chromatin remains in the form of nucleosomes) and not through male meiosis (where histones are replaced by protamines in a more widespread change in structure). The phenomena of imprinting and heterochromatic inactivation are combined in the case of X chromosome inactivation in female mammals. All X chromosomes but one are inactivated. Inactivation involves choice, initiation, propagation, and maintenance. The initiation mechanism involves coating the inactive X chromosome with Xist RNA; expression of Xist on the active chromosome is turned off by methylation of the promoter. Changes to chromatin occur on the inactive X chromosome, including changes in histone acetylation. But maintenance of the inactive state does not require Xist RNA, which suggests that the RNA is part of an unusual mechanism for creating a self-perpetuating state of which it is not itself part (for review see Panning and Jaenisch, 1998). Many epigenetic effects are observed in unusual situations—for example, when a gene is translocated into a position adjacent to heterochromatin. However, epigenetic control of gene expression also plays a role in normal development. Pc-G (Polycomb group) proteins in Drosophila are not conventional repressors, because they do not determine the initial pattern of expression

of the genes on which they act. In the absence of Pc-G proteins, these genes are initially repressed as usual, but later in development the repression is lost unless Pc-G group proteins were able to function at an earlier stage. This suggests that the Pc-G proteins in some way recognize a state of repression when it is established, and then act to perpetuate it through cell division. The trithorax group (trxG) proteins have the opposite effect, by maintaining the active state of genes. Little is known about the actions of either Pc-G or trxG proteins, except that they depend upon specific sequence elements in DNA to bind to chromatin, where they influence gene expression over long distances (for review see Pirrotta, 1998). The continued presence of Pc-G is needed for its repressive effect, which could mean that there is a restricted window of opportunity for initiation (perhaps while other necessary components are available). There are some parallels to the phenotypes seen in position effect variegation, and there are also transacting effects. The importance of these effects in the present context is the implication that there are selfmaintaining properties that convey cellular memory, and that are necessary for normal embryonic development. The most extreme case of inheritance by protein conformation is presented by the prion (for review see Prusiner et al., 1998). The infectious agent (originally identified for the disease scrapie in sheep) consists exclusively of protein. The naı¨ve form of the protein is a normal constituent of brain (with no known function). The determined form causes neurological disease, and is infectious upon introduction into a naı¨ve animal in the sense that it can sponsor the conversion of naı¨ ve protein into the determined form. Species-specific changes in the sequence of the protein influence its infectivity; and mutations in the gene in man are associated with diseases that result from spontaneous conversion into the determined form. The existence of different “strains” of scrapie that have the same sequence suggest that there are several possible states for the infective agent (typically as characterized by the duration of the period before infected mice display symptoms of disease). This implies that there are multiple conformations of the agent, each of which can impose itself by some templating effect on naı¨ve (newly synthesized) protein subunits. The validity of the general model for inheritance by protein conformation is supported by psi inheritance in yeast, in which a translation factor can effectively be sequestered in an inactive conformation as the result of an epigenetic conversion of its protein conformation (for review see Lindquist, 1997). In these cases, the conversion may be a unidirectional process: the epigenetic state can be reversed by loss of the agent, but the agent itself does not revert to the naı¨ve state. The occurrence of reversible epigenetic effects can imply that a structure can be created de novo, when the transition from the naı¨ve to the determined state occurs spontaneously (albeit at much lower frequency than the conversion nucleated by a preexisting determined state). But the existence of self-templating structures also raises the reverse question: are there structures that cannot be assembled de novo from their components but that must have a preexisting template? Indications

Overview 303

for such effects are found at centromeres, where it appears that the presence of the appropriate DNA sequences does not necessarily lead to kinetochore assembly (for review see Wiens and Sorger, 1998). One interesting example is provided by animal cell centromeres that consist largely of a satellite DNA. However, a DNA cannot be used to generate an active centromere de novo. If the a DNA is indeed the active component, this must mean that existing centromeres have an epigenetic structure that is not determined simply by the sequence (for review see Murphy and Karpen, 1998). Does this apply to other cellular components such as centrioles? This prompts the general question: to what extent does cell structure depend on preexisting templates for macromolecular assemblies or organelles that lack the intrinsic information necessary to form the determined structure? References Ekwall, K., Olsson, T., Turner, B.M., Cranston, G., and Allshire, R.C. (1997). Cell 91, 1021–1032. Cavalli, G., and Paro, R. (1998). Cell, in press. Colot, V., Maloisel, L., and Rossignol, J.-L. (1996). Cell 86, 855–864. Grunstein, M. (1998). Cell 93, this issue, 325–328. Henikoff, S., and Comai, L. (1998). Cell 93, this issue, 329–332. Lindquist, S. (1997). Cell 89, 495–498. Murphy, T.D., and Karpen, G. (1998). Cell 93, this issue, 317–320. Panning, B., and Jaenisch, R. (1998). Cell 93, this issue, 305–308. Pirrotta, V. (1998). Cell 93, this issue, 333–336. Prusiner, S., Scott, M.R., DeArmond, S.J., and Cohen, F.E. (1998). Cell 93, this issue, 337–348. Surani, A. (1998). Cell 93, this issue, 309–312. Wakimoto, B.T. (1998). Cell 93, this issue, 321–324. Wiens, G.R., and Sorger, P.K. (1998). Cell 93, this issue, 313–316.

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May 1, 1998 - genetics that two alleles can have the same genetic .... stage. This suggests that the Pc-G proteins in some way recognize a state of repression when it is estab- ... sequence of the protein influence its infectivity; and mu-.

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