The Metabolic Impact on Histone Acetylation and Transcription in Ageing

乙酰化 表观遗传学 老化 组蛋白 染色质 SIRT6型 组蛋白H3 衰老 基因表达调控 基因表达 细胞生物学 生物 锡尔图因 遗传学 基因
作者
Shahaf Peleg,Christian Feller,Andreas G. Ladurner,Axel Imhof
出处
期刊:Trends in Biochemical Sciences [Elsevier]
卷期号:41 (8): 700-711 被引量:157
标识
DOI:10.1016/j.tibs.2016.05.008
摘要

Aging animals show global, often nonspecific changes in gene expression. Epigenetic marks such as the acetylation of histones change substantially when animals age. These changes can already be observed when animals reach midlife. Changes in key metabolites during early aging result in changes in post-translational modifications of metabolic enzymes. This potentially leads to a transient increase in metabolic activity when animals reach midlife. Age-dependent changes of histone acetylation are coupled to altered metabolic activity in aging animals, which could potentially influence global gene expression. Mutations in genes that link metabolism and chromatin, such as lysine acetyl transferases (KATs), lysine deacetylases (KDACs) (sirtuins), and ATP citrate lyase (ACLY/ATPCL), have been shown to influence lifespan and the development of age-associated diseases. Loss of cellular homeostasis during aging results in altered tissue functions and leads to a general decline in fitness and, ultimately, death. As animals age, the control of gene expression, which is orchestrated by multiple epigenetic factors, degenerates. In parallel, metabolic activity and mitochondrial protein acetylation levels also change. These two hallmarks of aging are effectively linked through the accumulating evidence that histone acetylation patterns are susceptible to alterations in key metabolites such as acetyl-CoA and NAD+, allowing chromatin to function as a sensor of cellular metabolism. In this review we discuss experimental data supporting these connections and provide a context for the possible medical and physiological relevance. Loss of cellular homeostasis during aging results in altered tissue functions and leads to a general decline in fitness and, ultimately, death. As animals age, the control of gene expression, which is orchestrated by multiple epigenetic factors, degenerates. In parallel, metabolic activity and mitochondrial protein acetylation levels also change. These two hallmarks of aging are effectively linked through the accumulating evidence that histone acetylation patterns are susceptible to alterations in key metabolites such as acetyl-CoA and NAD+, allowing chromatin to function as a sensor of cellular metabolism. In this review we discuss experimental data supporting these connections and provide a context for the possible medical and physiological relevance. Several of the classical hallmarks of aging [1López-Otín C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar] correlate with epigenetic alterations that regulate transcription. Aged animals frequently show changes in gene expression [2Zahn J.M. Kim S.K. Systems biology of aging in four species.Curr. Opin. Biotechnol. 2007; 18: 355-359Crossref PubMed Scopus (40) Google Scholar], increased genomic instability, an erosion of telomeres, and increased cellular senescence [3O'Sullivan R.J. Karlseder J. Telomeres: protecting chromosomes against genome instability.Nat. Rev. Mol. Cell Biol. 2010; 11: 171-181Crossref PubMed Scopus (0) Google Scholar]. These distinct hallmarks functionally interact with each other and affect other hallmarks such as mitochondrial dysfunction or deregulated nutrient sensing. A current challenge is to identify the functional and temporal hierarchy among these hallmarks to shed light on the connectivity of the underlying molecular processes. Such insight might allow us to identify intervention strategies that target the early stages of the aging-associated decline. Despite the frequently observed correlation between animal aging and epigenetic changes [4Benayoun B.A. et al.Epigenetic regulation of ageing: linking environmental inputs to genomic stability.Nat. Rev. Mol. Cell Biol. 2015; 16: 593-610Crossref PubMed Scopus (96) Google Scholar], the molecular mechanisms that cause these alterations are far from being understood. In this review we focus on recent data describing how acetyl-CoA metabolism and histone acetylation could lead to an age-associated disruption of the transcriptome thereby affecting animal lifespan. This intricate connection between metabolism and chromatin also influences aging-associated tissue degeneration and dysfunction. However, due to space constraints we mainly discuss its impact on lifespan. Multiple studies have reported that alterations in the transcriptional output affect apparently unrelated genes [2Zahn J.M. Kim S.K. Systems biology of aging in four species.Curr. Opin. Biotechnol. 2007; 18: 355-359Crossref PubMed Scopus (40) Google Scholar, 5Pletcher S.D. et al.Genome-wide transcript profiles in aging and calorically restricted Drosophila melanogaster.Curr. Biol. 2002; 12: 712-723Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar] (Figure 1). Consistent with a stochastic loss of transcriptional control during aging, single-cell analysis of heart muscle tissue from young and old mice showed an increased cell-to-cell variation in transcription [6Bahar R. et al.Increased cell-to-cell variation in gene expression in ageing mouse heart.Nature. 2006; 441: 1011-1014Crossref PubMed Scopus (288) Google Scholar]. In yeast such error-prone transcription has been shown to result in proteotoxic stress and a shortened cellular lifespan [7Vermulst M. et al.Transcription errors induce proteotoxic stress and shorten cellular lifespan.Nat. Commun. 2015; 6: 8065Crossref PubMed Scopus (0) Google Scholar]. Such a general change in transcription may be indicative of a general loss in chromatin structure. Aging flies show a loss of transcriptional repression of transposable elements in the adult brain, indicating a deterioration of heterochromatin [8Li W. et al.Activation of transposable elements during aging and neuronal decline in Drosophila.Nat. Neurosci. 2013; 16: 529-531Crossref PubMed Scopus (78) Google Scholar]. Such a loss of repression of otherwise silenced repetitive DNA chromatin has also been observed in liver and muscle tissue of old mammals [9De Cecco M. et al.Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues.Aging (Albany NY). 2013; 5: 867-883Crossref PubMed Scopus (132) Google Scholar]. A role of repressive chromatin in counteracting organismal aging is also supported by the recent finding that mutations impairing heterochromatin stability result in a premature aging phenotype [10Larson K. et al.Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis.PLoS Genet. 2012; 8: e1002473Crossref PubMed Scopus (0) Google Scholar]. The lack of repression as indicated by increased transposon activity is also observed in senescent mammalian cells [11De Cecco M. et al.Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements.Aging Cell. 2013; 12: 247-256Crossref PubMed Scopus (93) Google Scholar], which have been proposed to contribute to organismal aging. This correlation between aging and cellular senescence has been suggested to occur due to impaired cellular homeostasis mediated either by a disruption of the stem cell niche or by the induction of an inflammatory response through the secretion of proinflammatory growth factors and cytokines [12van Deursen J.M. The role of senescent cells in ageing.Nature. 2014; 509: 439-446Crossref PubMed Scopus (324) Google Scholar]. Interestingly, senescent cells form so-called senescence-associated heterochromatin foci (SAHFs), which have been suggested to be caused by increased levels of repressive heterochromatin in these cells [13Funayama R. Ishikawa F. Cellular senescence and chromatin structure.Chromosoma. 2007; 116: 431-440Crossref PubMed Scopus (0) Google Scholar]. This is in apparent contradiction to the increased transcription of transposable elements that is usually repressed by heterochromatin [11De Cecco M. et al.Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements.Aging Cell. 2013; 12: 247-256Crossref PubMed Scopus (93) Google Scholar]. A hypothesis that could possibly explain this contradiction is that the loss of repression at repetitive DNA is induced by a redistribution of known heterochromatic factors from classic heterochromatin to SAHFs in senescent cells (Figure 1). An accumulation of senescent cells in an organism is very likely to have a negative impact on lifespan as it was recently shown that clearance of senescent cells in mice is linked with a substantial increase in lifespan [14Baker D.J. et al.Naturally occurring p16Ink4a-positive cells shorten healthy lifespan.Nature. 2016; 530: 184-189Crossref PubMed Scopus (269) Google Scholar]. In addition to showing a general impairment of transcriptional regulation, aging animals also show increases in aberrant RNA splicing [15Harries L.W. et al.Human aging is characterized by focused changes in gene expression and deregulation of alternative splicing.Aging Cell. 2011; 10: 868-878Crossref PubMed Scopus (81) Google Scholar]. Considering that chromatin structure has been shown to be involved in the regulation of alternative splicing [16Schwartz S. et al.Chromatin organization marks exon–intron structure.Nat. Struct. Mol. Biol. 2009; 16: 990-995Crossref PubMed Scopus (0) Google Scholar, 17Luco R.F. et al.Epigenetics in alternative pre-mRNA splicing.Cell. 2011; 144: 16-26Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar], chromatin structure changes during aging may thus contribute to alternative splicing. In addition to a loss in transcriptional precision that affects genes in a random manner, in some cases specific pathways also appear altered in aged animals [2Zahn J.M. Kim S.K. Systems biology of aging in four species.Curr. Opin. Biotechnol. 2007; 18: 355-359Crossref PubMed Scopus (40) Google Scholar, 5Pletcher S.D. et al.Genome-wide transcript profiles in aging and calorically restricted Drosophila melanogaster.Curr. Biol. 2002; 12: 712-723Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar]. A mutation in the histone demethylase UTX1, for example, delays aging in worms by targeting the insulin/IGF-1 signaling pathway [18Jin C. et al.Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway.Cell Metab. 2011; 14: 161-172Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Moreover, genes associated with inflammation and stress are often upregulated in old animals, while genes encoding mitochondrial and lysosome functions are reduced [2Zahn J.M. Kim S.K. Systems biology of aging in four species.Curr. Opin. Biotechnol. 2007; 18: 355-359Crossref PubMed Scopus (40) Google Scholar, 19de Magalhães J.P. et al.Meta-analysis of age-related gene expression profiles identifies common signatures of aging.Bioinformatics. 2009; 25: 875-881Crossref PubMed Scopus (286) Google Scholar]. These observations underpin the complexity of the underlying changes in chromatin-transcriptional pathways during aging. The histone proteins both package the DNA and participate in gene expression regulation. It has been previously shown that old human cells have reduced histone synthesis [20O'Sullivan R.J. et al.Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres.Nat. Struct. Mol. Biol. 2010; 17: 1218-1225Crossref PubMed Scopus (156) Google Scholar, 21Hu Z. et al.Nucleosome loss leads to global transcriptional up-regulation and genomic instability during yeast aging.Genes Dev. 2014; 28: 396-408Crossref PubMed Scopus (58) Google Scholar] and that elevated histone expression results in lifespan extension in Saccharomyces cerevisiae [22Feser J. et al.Elevated histone expression promotes life span extension.Mol. Cell. 2010; 39: 724-735Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar]. In addition, specific histone variants such as macroH2A or H3.3 and its proteolytically processed form have been suggested to contribute to senescence [23Zhang R. et al.Formation of macroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.Dev. Cell. 2005; 8: 19-30Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 24Duarte L.F. et al.Histone H3.3 and its proteolytically processed form drive a cellular senescence programme.Nat. Commun. 2014; 5: 1-12Crossref Scopus (0) Google Scholar]. An important aspect of histone biology is their potential to acquire a rich landscape of various post-translational modifications that affect their interaction with DNA or chromatin-associated proteins. These modifications have been shown to play a major role in the establishment and maintenance of specific gene expression profiles [25Kouzarides T. Chromatin modifications and their function.Cell. 2007; 128: 693-705Abstract Full Text Full Text PDF PubMed Scopus (5622) Google Scholar]. Besides being involved in transcriptional activation or repression, histone modifications affect transcriptional fidelity through the regulation of alternative splicing events [17Luco R.F. et al.Epigenetics in alternative pre-mRNA splicing.Cell. 2011; 144: 16-26Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar] or the inhibition of initiation from cryptic promoters [26Carrozza M.J. et al.Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription.Cell. 2005; 123: 581-592Abstract Full Text Full Text PDF PubMed Scopus (763) Google Scholar]. It is therefore conceivable that the observed loss in transcriptional precision is causally related to a change in histone modifications. A point mutant in lysine 36 of histone H3, a residue that is otherwise methylated to prevent transcription from cryptic promoters within coding regions, results in lifespan shortening in yeast [27Sen P. et al.H3K36 methylation promotes longevity by enhancing transcriptional fidelity.Genes Dev. 2015; 29: 1362-1376Crossref PubMed Scopus (36) Google Scholar]. Moreover, while reducing levels of H3K36 demethylases also increases lifespan in yeast and Caenorhabditis elegans, mutations in the H3K4 methyltransferases reduce lifespan [27Sen P. et al.H3K36 methylation promotes longevity by enhancing transcriptional fidelity.Genes Dev. 2015; 29: 1362-1376Crossref PubMed Scopus (36) Google Scholar, 28Ni Z. et al.Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans.Aging Cell. 2012; 11: 315-325Crossref PubMed Scopus (0) Google Scholar]. Importantly, while these studies show that the loss of transcription fidelity during aging can be counteracted by modulating the activities of specific histone-modifying enzymes in yeast and worms, whether similar intervention strategies would work in mammals and in humans needs to be further tested [29Mouchiroud L. et al.The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell. 2013; 154: 430-441Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar]. In the following, we discuss the connection between histone acetylation, cellular metabolism, and aging in detail. Histone acetylation promotes transcription by weakening electrostatic interactions between DNA and histones and between adjacent nucleosomes within a nucleosomal fiber [30Shogren-Knaak M. et al.Histone H4-K16 acetylation controls chromatin structure and protein interactions.Science. 2006; 311: 844-847Crossref PubMed Scopus (1017) Google Scholar] In addition, acetylated histones form recognition sites for bromodomain-containing proteins, which are often found in transcriptional coregulators [31Jacobson R.H. et al.Structure and function of a human TAFII250 double bromodomain module.Science. 2000; 288: 1422-1425Crossref PubMed Scopus (583) Google Scholar]. Acetylated histones are enriched over active genes and recruitment of lysine acetyltransferases (KATs), also referred to as histone acetyltransferases (HATs), increases transcription in vitro and in vivo [32Akhtar A. Becker P.B. Activation of transcription through histone H4 acetylation by MOF, an acetyltransferase essential for dosage compensation in Drosophila.Mol. Cell. 2000; 5: 367-375Abstract Full Text Full Text PDF PubMed Google Scholar, 33Utley R.T. et al.Transcriptional activators direct histone acetyltransferase complexes to nucleosomes.Nature. 1998; 394: 498-502Crossref PubMed Scopus (0) Google Scholar]. According to the prevailing view, histone acetylation functions largely through the cumulative charge effects of many individual acetylation events as, at least in vitro, bromodomains discriminate rather weakly between individual acetylation sites [31Jacobson R.H. et al.Structure and function of a human TAFII250 double bromodomain module.Science. 2000; 288: 1422-1425Crossref PubMed Scopus (583) Google Scholar, 34Dhalluin C. et al.Structure and ligand of a histone acetyltransferase bromodomain.Nature. 1999; 399: 491-496Crossref PubMed Scopus (937) Google Scholar, 35Dion M.F. et al.Genomic characterization reveals a simple histone H4 acetylation code.Proc. Natl Acad. Sci. U. S. A. 2005; 102: 5501-5506Crossref PubMed Scopus (0) Google Scholar, 36Ruthenburg A.J. et al.Multivalent engagement of chromatin modifications by linked binding modules.Nat. Rev. Mol. Cell Biol. 2007; 8: 983-994Crossref PubMed Scopus (645) Google Scholar]. However, recent studies challenge this view and indicate that some of the described redundancies are due to limited specificity of acetylation-directed antibodies (Box 1). For example, most acetylation antibodies show a strong polyacetylation bias and many H3 and H4 acetylation antibodies only weakly discriminate among single individual acetylation events [37Rothbart S.B. et al.An interactive database for the assessment of histone antibody specificity.Mol. Cell. 2015; 59: 502-511Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar].Box 1Methods for Studying Histone Modifications: Challenges and Recent Technical ProgressHistone modifications are commonly monitored with antibodies. The development of antibodies with affinity towards specific histone modifications at specific amino acids ('sites') in the early 1990s revolutionized research on chromatin biology [110Turner B.M. et al.Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei.Cell. 1992; 69: 375-384Abstract Full Text PDF PubMed Google Scholar, 111Hebbes T.R. et al.Histone acetylation and globin gene switching.Nucleic Acids Res. 1992; 20: 1017-1022Crossref PubMed Google Scholar]. However, the generation of modification-specific antibodies is difficult because modifications like acetylation and methylation add only minor chemical alterations to the epitope recognized by the antibody.Recent evidence raises considerable caution regarding the specificity of these antibodies and hence the interpretation of the data acquired using these reagents [37Rothbart S.B. et al.An interactive database for the assessment of histone antibody specificity.Mol. Cell. 2015; 59: 502-511Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 112Rothbart S.B. et al.Poly-acetylated chromatin signatures are preferred epitopes for site-specific histone H4 acetyl antibodies.Sci. Rep. 2012; 2: 489Crossref PubMed Scopus (23) Google Scholar]. Antibody binding is often modulated by adjacent modifications, resulting in crossreactivities among similar peptide sequences (e.g., H3K9 and H3K27 are embedded in the same ARKS motif), and lysine methylation-directed antibodies frequently crossreact towards lower methylation states. Moreover, polyclonal antibodies can have substantial lot-to-lot variations, which can be reduced with recombinant antibodies [113Hattori T. et al.Recombinant antibodies to histone post-translational modifications.Nat. Methods. 2013; 10: 992-995Crossref PubMed Scopus (0) Google Scholar]. In summary, strict antibody-validation procedures must be applied to assess the specificity of these reagents and allow biological interpretation.Mass spectrometry offers an alternative method to study histone modifications. Mass spectrometry enables identification of new modification types and sites, the reliable quantification of extensive sets of modifications in one experiment, the identification of co-occurring modifications within the same protein sequence, and the identification of protein-binding domains with affinity towards modified peptides or nucleosomes [114Soldi M. Bonaldi T. The proteomic investigation of chromatin functional domains reveals novel synergisms among distinct heterochromatin components.Mol. Cell. Proteomics. 2013; 12: 764-780Crossref PubMed Scopus (30) Google Scholar, 115Karch K.R. et al.Identification and interrogation of combinatorial histone modifications.Front. Genet. 2013; 4: 264Crossref PubMed Scopus (0) Google Scholar]. However, it lacks the spatial resolution of antibody-based ChIP approaches to map histone modifications to single genomic loci. To alleviate these shortcomings, hybrid methods such as proteomics of isolated chromatin segments (PICh) or nascent chromatin capture (NCC) have been developed to quantify proteins and histone modifications at abundant genomic regions [116Saksouk N. et al.Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation.Mol. Cell. 2014; 56: 580-594Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar] or newly replicated DNA [117Alabert C. et al.Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components.Nat. Cell Biol. 2014; 16: 281-293Crossref PubMed Scopus (102) Google Scholar, 118Alabert C. et al.Two distinct modes for propagation of histone PTMs across the cell cycle.Genes Dev. 2015; 29: 585-590Crossref PubMed Scopus (84) Google Scholar]. Moreover, the development of intracellular histone-modification-specific binders [119Stasevich T.J. et al.Regulation of RNA polymerase II activation by histone acetylation in single living cells.Nature. 2014; 516: 272-275Crossref PubMed Scopus (82) Google Scholar] and reader domain-based affinity reagents [120Wilkinson A.W. Gozani O. Histone-binding domains: strategies for discovery and characterization.Biochim. Biophys. Acta. 2014; 1839: 669-675Crossref PubMed Scopus (0) Google Scholar] offer complementary strategies to traditional antibody-based and mass spectrometry strategies. The application of these methods will help us better understand how altered histone acetylation pathways contribute to aging and aging-associated diseases, allowing the field to establish how chromatin-modification-based epigenetic changes are coupled to other hallmarks of aging [1López-Otín C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar]. Histone modifications are commonly monitored with antibodies. The development of antibodies with affinity towards specific histone modifications at specific amino acids ('sites') in the early 1990s revolutionized research on chromatin biology [110Turner B.M. et al.Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei.Cell. 1992; 69: 375-384Abstract Full Text PDF PubMed Google Scholar, 111Hebbes T.R. et al.Histone acetylation and globin gene switching.Nucleic Acids Res. 1992; 20: 1017-1022Crossref PubMed Google Scholar]. However, the generation of modification-specific antibodies is difficult because modifications like acetylation and methylation add only minor chemical alterations to the epitope recognized by the antibody. Recent evidence raises considerable caution regarding the specificity of these antibodies and hence the interpretation of the data acquired using these reagents [37Rothbart S.B. et al.An interactive database for the assessment of histone antibody specificity.Mol. Cell. 2015; 59: 502-511Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 112Rothbart S.B. et al.Poly-acetylated chromatin signatures are preferred epitopes for site-specific histone H4 acetyl antibodies.Sci. Rep. 2012; 2: 489Crossref PubMed Scopus (23) Google Scholar]. Antibody binding is often modulated by adjacent modifications, resulting in crossreactivities among similar peptide sequences (e.g., H3K9 and H3K27 are embedded in the same ARKS motif), and lysine methylation-directed antibodies frequently crossreact towards lower methylation states. Moreover, polyclonal antibodies can have substantial lot-to-lot variations, which can be reduced with recombinant antibodies [113Hattori T. et al.Recombinant antibodies to histone post-translational modifications.Nat. Methods. 2013; 10: 992-995Crossref PubMed Scopus (0) Google Scholar]. In summary, strict antibody-validation procedures must be applied to assess the specificity of these reagents and allow biological interpretation. Mass spectrometry offers an alternative method to study histone modifications. Mass spectrometry enables identification of new modification types and sites, the reliable quantification of extensive sets of modifications in one experiment, the identification of co-occurring modifications within the same protein sequence, and the identification of protein-binding domains with affinity towards modified peptides or nucleosomes [114Soldi M. Bonaldi T. The proteomic investigation of chromatin functional domains reveals novel synergisms among distinct heterochromatin components.Mol. Cell. Proteomics. 2013; 12: 764-780Crossref PubMed Scopus (30) Google Scholar, 115Karch K.R. et al.Identification and interrogation of combinatorial histone modifications.Front. Genet. 2013; 4: 264Crossref PubMed Scopus (0) Google Scholar]. However, it lacks the spatial resolution of antibody-based ChIP approaches to map histone modifications to single genomic loci. To alleviate these shortcomings, hybrid methods such as proteomics of isolated chromatin segments (PICh) or nascent chromatin capture (NCC) have been developed to quantify proteins and histone modifications at abundant genomic regions [116Saksouk N. et al.Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation.Mol. Cell. 2014; 56: 580-594Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar] or newly replicated DNA [117Alabert C. et al.Nascent chromatin capture proteomics determines chromatin dynamics during DNA replication and identifies unknown fork components.Nat. Cell Biol. 2014; 16: 281-293Crossref PubMed Scopus (102) Google Scholar, 118Alabert C. et al.Two distinct modes for propagation of histone PTMs across the cell cycle.Genes Dev. 2015; 29: 585-590Crossref PubMed Scopus (84) Google Scholar]. Moreover, the development of intracellular histone-modification-specific binders [119Stasevich T.J. et al.Regulation of RNA polymerase II activation by histone acetylation in single living cells.Nature. 2014; 516: 272-275Crossref PubMed Scopus (82) Google Scholar] and reader domain-based affinity reagents [120Wilkinson A.W. Gozani O. Histone-binding domains: strategies for discovery and characterization.Biochim. Biophys. Acta. 2014; 1839: 669-675Crossref PubMed Scopus (0) Google Scholar] offer complementary strategies to traditional antibody-based and mass spectrometry strategies. The application of these methods will help us better understand how altered histone acetylation pathways contribute to aging and aging-associated diseases, allowing the field to establish how chromatin-modification-based epigenetic changes are coupled to other hallmarks of aging [1López-Otín C. et al.The hallmarks of aging.Cell. 2013; 153: 1194-1217Abstract Full Text Full Text PDF PubMed Scopus (1852) Google Scholar]. Antibody-independent approaches suggest that acetylation sites and the combinatorial patterns they form with adjacent modifications bear more specific functions (Box 1). The binding of bromodomains to acetylated lysines, for example, is strongly modulated by adjacent modifications, including acetylation, methylation, and phosphorylation [38Filippakopoulos P. et al.Histone recognition and large-scale structural analysis of the human bromodomain family.Cell. 2012; 149: 214-231Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 39Morinière J. et al.Cooperative binding of two acetylation marks on a histone tail by a single bromodomain.Nature. 2009; 461: 664-668Crossref PubMed Scopus (224) Google Scholar]. In line with these findings, we recently suggested that the action of many acetyltransferases may be modulated by flanking modifications. This conclusion is based on measuring the abundance changes of histone acetylation patterns by mass spectrometry after systematically depleting all known or suspected acetyltransferases that are expressed in Drosophila melanogaster Kc cells [40Feller C. et al.Global and specific responses of the histone acetylome to systematic perturbation.Mol. Cell. 2015; 57: 559-571Abstract Full Text Full Text PDF PubMed Google Scholar, 41Blasi T. et al.Combinatorial histone acetylation patterns are generated by motif-specific reactions.Cell Syst. 2016; 2: 49-58Abstract Full Text Full Text PDF PubMed Google Scholar]. Altered histone acetylation patterns have been observed in aging tissues and are associated with age-related maladies such as cancer, neurodegeneration, and others [4Benayoun B.A. et al.Epigenetic regulation of ageing: linking environmental inputs to genomic stability.Nat. Rev. Mol. Cell Biol. 2015; 16: 593-610Crossref PubMed Scopus (96) Google Scholar, 42Dawson M.A. Kouzarides T. Cancer epigenetics: from mechanism to therapy.Cell. 2012; 150: 12-27Abstract Full Text Full Text PDF PubMed Scopus (973) Google Scholar, 43G
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