Decoding the Epigenetic Language of Neuronal Plasticity
2008; Cell Press; Volume: 60; Issue: 6 Linguagem: Inglês
10.1016/j.neuron.2008.10.012
ISSN1097-4199
AutoresEmiliana Borrelli, Eric J. Nestler, C. David Allis, Paolo Sassone–Corsi,
Tópico(s)Neurogenesis and neuroplasticity mechanisms
ResumoNeurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. These unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. Epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. This review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. We outline the molecular pathways underlying chromatin transitions, propose the presence of an "epigenetic indexing code," and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function. Neurons are submitted to an exceptional variety of stimuli and are able to convert these into high-order functions, such as storing memories, controlling behavior, and governing consciousness. These unique properties are based on the highly flexible nature of neurons, a characteristic that can be regulated by the complex molecular machinery that controls gene expression. Epigenetic control, which largely involves events of chromatin remodeling, appears to be one way in which transcriptional regulation of gene expression can be modified in neurons. This review will focus on how epigenetic control in the mature nervous system may guide dynamic plasticity processes and long-lasting cellular neuronal responses. We outline the molecular pathways underlying chromatin transitions, propose the presence of an "epigenetic indexing code," and discuss how central findings accumulating at an exponential pace in the field of epigenetics are conceptually changing our perspective of adult brain function. The ability to store information over long periods of time lies at the heart of cellular identity. This cellular "memory" is encoded in the specific pattern of expressed genes and allows a cell to ensure that it "remembers" who it is and how it should move along elaborate pathways during cellular development and differentiation. During development, germ cells or totipotent stem cells give rise to a diverse array of specialized cell types, including nerve cells, which become more hard-wired. These changes allow specialized cells to appropriately function in their specific niche—and, in the case of nerve cells, allows them to properly control cognitive and behavioral functions. Once cellular differentiation processes are established, postmitotic nerve cells become committed to a variety of highly specialized functions that collectively determine our responses to external stimuli. Yet, insults, injury, and neurodegenerative diseases can dramatically affect nerve cells, calling into place a poorly understood "reprogramming process" that may be able to erase previously established cellular settings and, possibly, dedifferentiate or revert these cells to a more primitive pluripotent state. Thus, it seems that developmental processes require "forward" differentiation with a built-in memory component as well as a "reversible" reprogramming capability, allowing for plasticity at many levels (anatomical, electrical, synaptic, etc.). How could one relatively fixed genetic blueprint permit this flexibility to accommodate variability resulting from signals originated from environmental, dietary, and other influences? How are cellular memories shaped by past experiences and environmental cues? Does a molecular "sculpturing" process exist during development and adult life that takes adaptive cues from the environment (i.e., epigenetic mechanisms), or is this molding process purely stochastic in nature with selection doing the rest (i.e., genetic mechanisms)? (Figure 1) The nervous system is characterized by a vast spectrum of cell types as well as a staggering number of reinforcing connections (synapses) that collectively shape and translate our daily experiences into complex thoughts and behaviors. Can ∼25,000 genes in our relatively fixed human genome explain who we are and how we act? A wealth of accumulating evidence suggests that there is much more to the genome than DNA sequence, permitting variability beyond the Watson-Crick DNA double helix. One way that such additional variability can be established is through epigenetic mechanisms (Figure 1). In this review, we explore the evidence that suggests that these mechanisms play a critical role in regulating neuronal function in the adult brain. A wealth of recent work from many laboratories has rekindled an interest in an old word: epigenetics. The general concept of an "epigenetic landscape" was first articulated by developmental biologist Conrad Waddington, who used it to explain how identical genotypes could unfold a wide collection of phenotypes as development proceeded (Waddington, 1957Waddington C.H. The Strategy of the Genes; a Discussion of Some Aspects of Theoretical Biology. Allen & Unwin, London1957Google Scholar). With time, Waddington's concept of a phenotypic landscape took on additional meaning: "potentially heritable changes in gene expression that do not involve changes in DNA sequence" (Holliday and Pugh, 1975Holliday R. Pugh J.E. DNA modification mechanisms and gene activity during development.Science. 1975; 187: 226-232Crossref PubMed Scopus (20) Google Scholar, Chambon, 1978Chambon P. The molecular biology of the eukaryotic genome is coming of age.Cold Spring Harb. Symp. Quant. Biol. 1978; 42: 1209-1234Crossref PubMed Google Scholar, Jaenisch and Bird, 2003Jaenisch R. Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.Nat. Genet. 2003; 33: 245-254Crossref PubMed Scopus (1948) Google Scholar). While important questions remain, Waddington's landscape has taken a clearer molecular form with the documentation of a remarkable number of multisubunit complexes that act to remodel chromatin—to exchange specific histones (histone variants) in and out of assembled chromatin—or to enzymatically modify DNA and histones to bring about downstream events. It is not fully clear how these dedicated machines are guided to their target sequences, but it is likely to involve constellations of cis-acting regulatory proteins and noncoding RNAs that engage the DNA template directly (Bernstein and Allis, 2005Bernstein E. Allis C.D. RNA meets chromatin.Genes Dev. 2005; 19: 1635-1655Crossref PubMed Scopus (328) Google Scholar). Some epigenetic marks, such as DNA methylation, appear to provide more stable, if not permanent, indexing marks that extend over long chromosomal domains, giving rise to "memorized" states of gene expression that may be inherited from one cell generation to the next (Figure 1). Other modifications, such as histone acetylation, may be more labile and mediate regulation of gene expression over shorter-term periods. Considering the staggering complexity of neurogenesis, to what extent do changes in synaptic connections, guided by experiences, environment, diet, etc., influence the epigenomes of postmitotic nerve cells that underlie animal behavior, normal or abnormal? Chromatin remodeling in the nervous system would not be directly heritable. Rather, heritability at this level could be through the reproducibility of behavioral patterns from a parent on its offspring. In this review, we concentrate on emerging findings that tie epigenetic pathways to the special requirements exhibited by nerve cells, specifically of having seemingly opposing mechanisms allowing for cellular "memory" as well as cellular "plasticity." Somewhat a reflection of our interests in chromatin remodeling, we focus our remarks on specific examples of how histone posttranslational modifications (PTMs) are "written," "erased," and "interpreted" in ways that might contribute to both stable and plastic neuronal properties (Figure 2). Of course it is expected that many variations on this general theme exist and that a multitude of interconnected molecular signaling pathways dictates the elaborate gene expression networks that direct the complexities of nerve cell function. Several broad questions can be posed at this juncture. Are PTMs suited for on-off behavior of short-lived, binary switches (Fischle et al., 2003Fischle W. Wang Y. Allis C.D. Binary switches and modification cassettes in histone biology and beyond.Nature. 2003; 425: 475-479Crossref PubMed Scopus (421) Google Scholar) belonging to a different set from the PTMs compatible with more lasting, graded responses? Are some PTMs, or the protein complexes that engage them, more compatible with short-term versus long-term memory, and is there enough combinatorial readout of PTMs to deal with the diversity and plasticity of neuronal cells? A wealth of histone PTMs has been uncovered in a variety of cell models. Our goal here was not to provide a compilation of them but to illustrate general principles as they might apply to the nervous system, by specifically highlighting distinct examples for further discussion, including synaptic transmission, behavioral memory, drug addiction, circadian rhythms, and mental retardation-autism syndromes. Numerous reviews on chromatin biology (Berger, 2007Berger S.L. The complex language of chromatin regulation during transcription.Nature. 2007; 447: 407-412Crossref PubMed Scopus (1026) Google Scholar, Lee and Workman, 2007Lee K.K. Workman J.L. Histone acetyltransferase complexes: one size doesn't fit all.Nat. Rev. Mol. Cell Biol. 2007; 8: 284-295Crossref PubMed Scopus (283) Google Scholar), DNA methylation (Miranda and Jones, 2007Miranda T.B. Jones P.A. DNA methylation: the nuts and bolts of repression.J. Cell. Physiol. 2007; 213: 384-390Crossref PubMed Scopus (207) Google Scholar), and noncoding RNAs (Bernstein and Allis, 2005Bernstein E. Allis C.D. RNA meets chromatin.Genes Dev. 2005; 19: 1635-1655Crossref PubMed Scopus (328) Google Scholar) have appeared in the literature (see Allis et al., 2007aAllis C.D. Jenuwein T. Reinberg D. Caparros M.L. Epigenetics. Cold Spring Harbor Laboratory Press, New York2007Google Scholar, for a textbook on epigenetics). Finally, a comprehensive nomenclature has been proposed for chromatin-modifying enzymes (Allis et al., 2007bAllis C.D. Berger S.L. Cote J. Dent S. Jenuwien T. Kouzarides T. Pillus L. Reinberg D. Shi Y. Shiekhattar R. et al.New nomenclature for chromatin modifying enzymes.Cell. 2007; 131: 633-636Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar). Chromatin contributes in ensuring that the storage, organization, and readout of the genetic information occurs in a proper spatial and temporal sequence during cellular differentiation and organismal development. The fundamental repeating unit of chromatin, the nucleosome core particle, consists of 147 bp of DNA organized in approximately two superhelical turns of DNA wrapped around an octamer of core histone proteins (two copies each of H2A, H2B, H3, and H4 or variants thereof). When associated with other components, higher-order nucleosomal structures are formed. Variations introduced into nucleosome array structures by a variety of mechanisms (see below) cause subtle, but meaningful, differences in chromatin compaction that correlate closely with more "open" versus "closed" states. These states loosely correlate with "euchromatin" versus "heterochromatin" states that often, but not always, align with "active" versus "inactive" states of gene expression, respectively (Berger, 2007Berger S.L. The complex language of chromatin regulation during transcription.Nature. 2007; 447: 407-412Crossref PubMed Scopus (1026) Google Scholar). Covalent histone modifications, histone variants, or chromatin remodeling complexes work together to alter the chromatin fiber (Cheung et al., 2000aCheung P. Allis C.D. Sassone-Corsi P. Signaling to chromatin through histone modifications.Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Google Scholar, Strahl and Allis, 2000Strahl B.D. Allis C.D. The language of covalent histone modifications.Nature. 2000; 403: 41-45Crossref PubMed Scopus (3943) Google Scholar). For example, histone acetylation, a charge-altering modification that negates the positive charge on the ɛ-amino groups of lysine, has long been correlated with transcriptional activation (Cheung et al., 2000aCheung P. Allis C.D. Sassone-Corsi P. Signaling to chromatin through histone modifications.Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Google Scholar), likely due to weakening of histone:DNA contacts. In contrast, histone hypoacetylation correlates closely with gene silencing (Lee and Workman, 2007Lee K.K. Workman J.L. Histone acetyltransferase complexes: one size doesn't fit all.Nat. Rev. Mol. Cell Biol. 2007; 8: 284-295Crossref PubMed Scopus (283) Google Scholar). For the purposes of this review, several well-studied PTMs serve to illustrate paradigms emerging in present-day chromatin biology, with neurobiologists only beginning to consider how these modifications contribute to neuronal functions (Crosio et al., 2003Crosio C. Heitz E. Allis C.D. Borrelli E. Sassone-Corsi P. Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons.J. Cell Sci. 2003; 116: 4905-4914Crossref PubMed Scopus (121) Google Scholar, Levenson and Sweatt, 2005Levenson J.M. Sweatt J.D. Epigenetic mechanisms in memory formation.Nat. Rev. Neurosci. 2005; 6: 108-118Crossref PubMed Scopus (313) Google Scholar, Tsankova et al., 2007Tsankova N. Renthal W. Kumar A. Nestler E.J. Epigenetic regulation in psychiatric disorders.Nat. Rev. Neurosci. 2007; 8: 355-367Crossref PubMed Scopus (538) Google Scholar). For example, acetylation and methylation result from the addition or removal of acetyl and methyl or groups enzymatically donated from respective high-energy donors (acetyl coenzymeA [acetyl-CoA] and S-adenosyl methionine [SAM]; see Table 1). Histones are acetylated by histone acetyltransferases (HATs), which comprise a large family of enzymes, and deacetylated by histone deacetylases (HDACs), which are divided in different families. Class I HDACs are believed to provide the major HDAC catalytic activity present in brain, which is then modified by class II HDACs through direct binding interactions. Class III HDACs represent a distinct subfamily, as discussed under circadian regulation below. Both histone H3 and H4 undergo polyacetylation at nearby lysine residues in the proteins' N termini; however, still much more needs to be uncovered about the targeted recruiting and specificity of individual HATs and HDACs involved in these reactions.Table 1Linking Histone Modifications to MetabolismPhosphorylationATP/ADPMethylationSAM/SAH, FAD/FADH2AcetylationAcetyl-CoA/CoA, NAD/NADH, Acetyl-ADP-riboseUbiquitylation/sumoylationglucose?GlycosylationUDP-GlcNAc/UDPPosttranslational modifications are elicited by specific enzymes whose activity depends on the intracellular levels of essential metabolites, thus sensing cellular metabolism, nutrients, and energy levels in the cell. PTMs target specific sites on histones, indicating that transient states of chromatin remodeling are under dynamic regulation of cellular physiology. Open table in a new tab Posttranslational modifications are elicited by specific enzymes whose activity depends on the intracellular levels of essential metabolites, thus sensing cellular metabolism, nutrients, and energy levels in the cell. PTMs target specific sites on histones, indicating that transient states of chromatin remodeling are under dynamic regulation of cellular physiology. Methylation affects DNA, RNA, and histone and nonhistone proteins, at least to varying degrees in different organisms. In some cases, intriguing links have emerged between histone modifications, and specifically methylation, and DNA methylation (Mutskov et al., 2002Mutskov V.J. Farrell C.M. Wade P.M. Wolffe A.P. Felsenfeld G. The barrier function of an insulator couples high histone acetylation levels with specific protection of promoter DNA from methylation.Genes Dev. 2002; 16: 1540-1554Crossref PubMed Scopus (122) Google Scholar, Ooi et al., 2007Ooi S.K. Qiu C. Bernstein E. Li K. Jia D. Yang Z. Erdjument-Bromage H. Tempst P. Lin S.P. Allis C.D. et al.DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.Nature. 2007; 448: 714-717Crossref PubMed Scopus (505) Google Scholar). Second, within any potential histone or nonhistone protein that is methylated, multiple lysines or arginines can be modified, often existing together in localized regions of the same or different histone domains. Thus, at least for lysine- and arginine-rich proteins like histones, a wealth of biological readouts may be possible. Third, and expanding on the complexity of methylation, individual lysine residues can be mono-, di-, or trimethylated; similarly, arginine residues can be mono- or dimethylated, and these can be dimethylated in a symmetric or asymmetric fashion. These various methylation reactions are mediated by distinct subtypes of histone methyltransferases and demethylases, as discussed in the next section. Note that, unlike acetylation, methylation does not alter the positive charge of the targeted lysine or arginine, suggesting potential differences in regulatory outputs. Fourth, methylation of distinct lysine residues has opposite functional consequences on gene activation (see below). Fifth, all of the core histones (Shi and Whetstine, 2007Shi Y. Whetstine J.R. Dynamic regulation of histone lysine methylation by demethylases.Mol. Cell. 2007; 25: 1-14Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar) are methylated depending upon the physiological setting. Moreover, in keeping with studies on acetylation, methylation is not limited to histone proteins. Nonhistone proteins, such as the tumor suppressor p53 (Huang et al., 2007Huang J. Sengupta R. Espejo A.B. Lee M.G. Dorsey J.A. Richter M. Opravil S. Shiekhattar R. Bedford M.T. Jenuwein T. Berger S.L. p53 is regulated by the lysine demethylase LSD1.Nature. 2007; 449: 105-108Crossref PubMed Scopus (226) Google Scholar, Shi et al., 2007Shi X. Kachirskaia I. Yamaguchi H. West L.E. Wen H. Wang E. Dutta S. Appella E. Gozani O. Modulation of p53 function by SET8 mediated methylation at lysine 382.Mol. Cell. 2007; 27: 636-646Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar), are physiological targets of methylation reactions, a growing list likely to cross over into neuronal-specific proteins. Thus, methylation alone provides a remarkable number of regulatory options to the cell (Ruthenburg et al., 2007aRuthenburg A.J. Li H. Patel D.J. Allis C.D. Multivalent engagement of chromatin modifications by linked binding modules.Nat. Rev. Mol. Cell Biol. 2007; 8: 983-994Crossref PubMed Scopus (412) Google Scholar). Combining methylation with other PTMs, such as acetylation, causes a remarkable array of possibilities. As discussed in the next paragraph, we favor a scenario where the controlled addition and removal of specific PTMs results into unique combinations that constitute a sort of "epigenetic indexing code" that corresponds to distinct physiological states and genomic functions. Remarkable progress has been made in characterizing what is often being referred to as "writers, readers, and erasers" of PTMs in histone and nonhistone proteins (Figure 2). Thus, considerable attention has been placed in documenting the global distribution (or "patterns") of histone PTMs using a variety of high-resolution genomic profiling methods (Bernstein et al., 2005Bernstein B.E. Kamal M. Lindblad-Toh K. Bekiranov S. Bailey D.K. Huebert D.J. McMahon S. Karlsson E.K. Kulbokas 3rd, E.J. Gingeras T.R. et al.Genomic maps and comparative analysis of histone modifications in human and mouse.Cell. 2005; 120: 169-181Abstract Full Text Full Text PDF PubMed Scopus (754) Google Scholar, Barski et al., 2007Barski A. Cuddapah S. Cui K. Roh T.Y. Schones D.E. Wang Z. Wei G. Chepelev I. Zhao K. High-resolution profiling of histone methylations in the human genome.Cell. 2007; 129: 823-837Abstract Full Text Full Text PDF PubMed Scopus (2313) Google Scholar). It emerges from these studies that "epigenomes" are highly organized and strikingly nonrandom with respect to histone and DNA modifications (reviewed in Bernstein et al., 2007Bernstein B.E. Meissner A. Lander E.S. The mammalian epigenome.Cell. 2007; 128: 669-681Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar). Evidence discussed in this review indicates that the enzymatic machinery that elicits these PTMs operates under the control of a variety of neuronal stimuli, which link physiological variations to modulated chromatin remodeling and thereby controlled gene expression (Figure 3). One important consideration relates to the intracellular pathways involved in the marking of these PTMs. Interestingly, all use physiological metabolites, thereby indicating that the dynamic process of chromatin remodeling may "sense" cellular metabolism and changes in energy levels (Table 1), which are highly controlled and functionally essential in neuronal responses. Selected combinations of numerous PTMs occur at specific residues of the histone H3 N-terminal tail (Figure 3). For example, high levels of H3 and H4 acetylation and H3 lysine 4 methylation (H3K4me) are generally present in promoter regions of active genes (Ruthenburg et al., 2007bRuthenburg A.J. Allis C.D. Wysocka J. Methylation of Lysine 4 on Histone H3: Intricacy of writing and reading a single epigenetic mark.Mol. Cell. 2007; 25: 15-30Abstract Full Text Full Text PDF PubMed Scopus (458) Google Scholar). In contrast, elevated levels of H3 lysine 27 (H3K27me) correlate with gene repression mediated by the protein Polycomb (Trojer and Reinberg, 2006Trojer P. Reinberg D. Histone lysine demethylases and their impact on epigenetics.Cell. 2006; 125: 213-217Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Interestingly, the "degree" of histone lysine methylation matters, with significant differences in large-scale patterns of mono-, di-, and trimethylation at specific lysine residues, whether activating or repressing (Barski et al., 2007Barski A. Cuddapah S. Cui K. Roh T.Y. Schones D.E. Wang Z. Wei G. Chepelev I. Zhao K. High-resolution profiling of histone methylations in the human genome.Cell. 2007; 129: 823-837Abstract Full Text Full Text PDF PubMed Scopus (2313) Google Scholar). These sorts of epigenetic indexing patterns vary in different cell types or during different stages of development (Marin-Husstege et al., 2002Marin-Husstege M. Muggironi M. Liu A. Casaccia-Bonnefil P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression.J. Neurosci. 2002; 22: 10333-10345Crossref PubMed Google Scholar, Lessard et al., 2007Lessard J. Wu J.I. Ranish J.A. Wan M. Winslow M.M. Staahl B.T. Wu H. Aebersold R. Graef I.A. Crabtree G.R. An essential switch in subunit composition of a chromatin remodeling complex during neural development.Neuron. 2007; 55: 201-215Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar, Putignano et al., 2007Putignano E. Lonetti G. Cancedda L. Ratto G. Costa M. Maffei L. Pizzorusso T. Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity.Neuron. 2007; 53: 747-759Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). For example, a "bivalent domain," characterized by a configuration of marking genes with both "ON" (H3K4me) and "OFF" (H3K27me), was noted in key developmental genes in embryonic stem cells (Bernstein et al., 2006Bernstein E. Duncan E.M. Masui O. Gil J. Heard E. Allis C.D. Mouse polycomb proteins bind differently to methylated histone H3 and RNA and are enriched in facultative heterochromatin.Mol. Cell. Biol. 2006; 26: 2560-2569Crossref PubMed Scopus (203) Google Scholar). How bivalent domains are resolved during development is not known. As well, the extent to which neuronal cells use the strategies of histone PTMs as part of a mechanism for establishing "epigenomes" underlying neuronal diversity is not clear. How does DNA methylation and noncoding RNA enter into the above equation? Recent findings suggest that all of these components work together to bring about a "language" that greatly exceeds that of DNA alone (Ooi and Henikoff, 2007Ooi S.L. Henikoff S. Germline histone dynamics and epigenetics.Curr. Opin. Cell Biol. 2007; 19: 257-265Crossref PubMed Scopus (60) Google Scholar). If histone methylation does not alter the charge of target lysines or arginines, how does histone methylation function? Unlike acetylation, where charge-based mechanisms are likely to apply, histone:DNA contacts might not be affected by histone methylation in what can be referred to as "cis" (structural) effects on nucleosome structure. Likely, histone methylation is "read" by effector proteins that bring about meaningful downstream events by "trans" mechanisms (Figure 2). Effector proteins contain "reader" modules that structural and functional evidence identify as relatively short (50–100 aa) binding motifs, such as chromodomains or PHD fingers, which read histone methyl-lysine marks with remarkable and elegant precision (Ruthenburg et al., 2007aRuthenburg A.J. Li H. Patel D.J. Allis C.D. Multivalent engagement of chromatin modifications by linked binding modules.Nat. Rev. Mol. Cell Biol. 2007; 8: 983-994Crossref PubMed Scopus (412) Google Scholar, Lee and Workman, 2007Lee K.K. Workman J.L. Histone acetyltransferase complexes: one size doesn't fit all.Nat. Rev. Mol. Cell Biol. 2007; 8: 284-295Crossref PubMed Scopus (283) Google Scholar). Similarly, as suggested in early articulations of the histone and epigenetic code hypotheses (Cheung et al., 2000aCheung P. Allis C.D. Sassone-Corsi P. Signaling to chromatin through histone modifications.Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Google Scholar, Strahl and Allis, 2000Strahl B.D. Allis C.D. The language of covalent histone modifications.Nature. 2000; 403: 41-45Crossref PubMed Scopus (3943) Google Scholar, Jenuwein and Allis, 2001Jenuwein T. Allis C.D. Translating the histone code.Science. 2001; 293: 1074-1080Crossref PubMed Scopus (4641) Google Scholar, Turner, 2002Turner B. Cellular memory and the histone code.Cell. 2002; 111: 285-291Abstract Full Text Full Text PDF PubMed Scopus (687) Google Scholar), specific acetyl-lysine marks are also read in histone and nonhistone proteins by bromodomains. Also, interplays exist between adjacent or neighboring modifications that may serve to govern the binding and interactions of the effector proteins (Fischle et al., 2003Fischle W. Wang Y. Allis C.D. Binary switches and modification cassettes in histone biology and beyond.Nature. 2003; 425: 475-479Crossref PubMed Scopus (421) Google Scholar). Understanding the extent to which such repeated modules read PTMs, either on a single histone tail or on multiple tails or even distinct nucleosomes, remains a challenge for future studies. The general stability of DNA and histone methylation marks, as compared to rapid turnover kinetics PTMs such as acetylation and phosphorylation (Figure 4), prompted early speculation that methylation might be the ideal epigenetic indexing system (Jenuwein and Allis, 2001Jenuwein T. Allis C.D. Translating the histone code.Science. 2001; 293: 1074-1080Crossref PubMed Scopus (4641) Google Scholar, Bannister and Kouzarides, 2005Bannister A.J. Kouzarides T. Reversing histone methylation.Nature. 2005; 436: 1103-1106Crossref PubMed Scopus (245) Google Scholar). While the situation with DNA demethylation remains unclear, with some reports of rapid DNA demethylation occurring in brain (Fan et al., 2001Fan G. Beard C. Chen R.Z. Csankovszki G. Sun Y. Siniaia M. Biniszkiewicz D. Bates B. Lee P.P. Kuhn R. et al.DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals.J. Neurosci. 2001; 21: 788-797Crossref PubMed Google Scholar, Miller and Sweatt, 2007Miller C.A. Sweatt J.D. Covalent modification of DNA regulates memory formation.Neuron. 2007; 53: 857-869Abstract Full Text Full Text PDF PubMed Scopus (390) Google Scholar), progress has been made in the area of histone demethylation. Demethylase activities are being described for essentially all of the well-known lysine methyl sites in histones, not to mention those that are selective for mono-, di-, or trimethylation states (Trojer and Reinberg, 2006Trojer P. Reinberg D. Histone lysine demethylases and their impact on epigenetics.Cell. 2006; 125: 213-217Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar), promising to carry this family of enzymes into the "celebrity status" of other chromatin modifiers, such as HATs and HDACs. Recent findings indicate that some of these enzymes turn out to be critical in neuronal functions. For example, the histone H3K4 tridemethylase SMCX links repression of target genes (e.g., the sodium channel type 2A and synapsin 1) to mental retardation and epilepsy (Tahiliani et al., 2007Tahiliani M. Mei P. Fang R. Leonor T. Rutenberg M. Shimizu F. Li J. Rao A. Shi Y. The histone H3K4 demethylase SMCX links REST target genes to Xlinked mental retardation.Nature. 2007; 447: 601-605Crossref PubMed Scopus (177) Google Scholar). These studies underscore several important points. First, they point to a general model wherein failure to remove, or most certainly add, "ON" epigenetic marks, such as H3K4me3 (or likely "OFF
Referência(s)