Current Molecular Biology Reports

, Volume 2, Issue 1, pp 26–35 | Cite as

Histone Modifications in Ageing and Lifespan Regulation

  • Monika Maleszewska
  • Julia S. P. Mawer
  • Peter TessarzEmail author
Epigenetics (J Davie and C Nelson, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Epigenetics


Ageing has been associated with structural changes in chromatin. At the molecular level, multiple histone modifications with established epigenetic mechanisms have been connected to the regulation of lifespan. Here, we review the changes in histone modification profiles during ageing and their possible functional contribution to ageing and lifespan regulation. We brief the state of the knowledge on marks associated with both repressive (H3K9me3, H3K9me2, H3K27me3) and active chromatin (H3K4me3, H3K36me3, H3K56ac, H4K16ac, H2Bub). We further explore new histone modifications that emerged as lifespan-regulating candidates from a recent screen in yeast. Next, we comment on protein arginine methylation and GlcNAcylation, exploring their potential links to ageing. Finally, we provide a perspective on integrative approaches and methodological advances that might aid our pursuit of the epigenetic mechanisms of ageing.


Epigenetics Histone modifications Chromatin Ageing 


Chromatin provides the scaffold for the packaging of the entire genome. The basic functional unit of chromatin is the nucleosome, which contains 147 base pairs of DNA wrapped around a histone octamer made up of two copies of each of the histone proteins H2A, H2B, H3, and H4.

Research over the last two decades has revealed that covalent modifications of both the histone proteins, and the underlying DNA, can alter the organization of chromatin. This opened the doors for researchers trying to understand the meaning of specific modifications, their role in controlling gene expression, and thereby cellular phenotypes.

In the last few years, the role of histone modifications in the process of ageing has emerged, providing insights into epigenetic mechanisms of ageing and lifespan regulation. Excellent reviews exist on the epigenetics of senescence and the roles of sirtuins or DNA-methylation in ageing [1, 2, 3, 4, 5]. In this review, we will focus on histone modifications, review the current state of knowledge, and provide perspective on their role in the regulation of organismal ageing and lifespan.

Histone Modifications Involved in Ageing and Lifespan Regulation

H3K9me3 and H3K9me2

Heterochromatin, the best-known form of repressed chromatin, is characterized by dense structure and absent or strongly diminished transcription. Histone-3 lysine-9 tri-methylation (H3K9me3) is the hallmark of constitutive heterochromatin, present in pericentromeric and telomeric regions [6]. Its di-methylated form, H3K9me2, besides heterochromatin can also mark inactive euchromatin, which is important in embryonic development [7, 8, 9]. Both H3K9me2 and H3K9me3 are able to recruit heterochromatin protein-1 (HP1), which is believed to advance heterochromatin formation [10, 11, 12].

Ageing associates with a decrease or redistribution of H3K9me3/2, disruption of HP1 localization, and restructuring of heterochromatin, with loss of repression over constitutive heterochromatin loci and concomitant gain in facultative heterochromatin in other genomic regions [13]. A “loss of heterochromatin” model of ageing has been proposed and corroborated by studies linking changes in heterochromatin to ageing phenotypes in Caenorhabditis elegans, Drosophila, and humans [13, 14, 15, 16, 17]. Studies in the models of premature ageing-related diseases also implicate the connection between changes in heterochromatin and ageing [17, 18, 19]. The debate on whether the mechanisms of premature ageing are equivalent to the mechanisms of natural ageing is still ongoing. Nonetheless, loss of H3K9me3, HP1, and the H3K9 methyltransferase, SUV39H1, has been observed in both Werner syndrome model cells and cells derived from old individuals, suggesting that these models may indeed provide clues relevant to the mechanism of physiological ageing [17].

The levels of H3K9me3 were reported to decrease with ageing in C. elegans, while the levels of H3K9me2 and HP1 decreased in aged Drosophila [16, 20]. Interestingly, Wood et al. observed an increase in total H3K9me3 levels, and no change in HP1 expression, in aged flies [21]. They showed instead that the H3K9me3 mark seems to be redistributed, leading to even distribution of H3K9me3 (and HP1) levels between heterochromatin and euchromatin [21]. This redistribution within different chromatin regions coincided with altered nuclear localization of H3K9me3 and HP1 [21]. This study therefore corroborates the idea that ageing is accompanied by restructuring of heterochromatin and redistribution of H3K9me3/2 and HP1, rather than by simple change in their abundance.


While H3K9me3 is strongly associated with the constitutive heterochromatin repressed in all cell types (e.g. pericentromeric regions), H3K27me3 is found in facultative heterochromatin regions whose repression is more cell-type-specific. H3K27me3 seems to be more dynamically modified to allow repression or derepression of groups of genes during development or differentiation [22].

Levels of H3K27me3 were reported to decrease with age in C. elegans [20, 23]. Knockdown of the H3K27me3 demethylase UTX-1 (homologous to the mammalian UTX/KDM6A) increased worms’ H3K27me3 levels and extended their lifespan [23]. UTX-1 expression normally increases with age in worms and in human brain [24]. Low UTX-1 expression corresponds to the higher levels of H3K27me3 at the promoter of Igf1r, member of the highly conserved ageing-related insulin/IGF-1 pathway. Repression of this pathway by the UTX-1/H3K27me3 axis might therefore also be conserved between species [24]. Interestingly, another known H3K27me3 demethylase, JMJD3/KDM6B, has not yet been connected to ageing, although it is known to control expression from the senescence-associated p16INK4A locus [25, 26]. Surprisingly, histone methyltransferase set-26 that normally deposits methylation marks on H3K27 and H3K9 was necessary for the age-related loss of H3K27me3 in C. elegans [20]. Set-26 knockdown prevented the age-related decrease in H3K27me3 (and H3K9me3) and increased worm’s longevity [20]. Overall, the studies in C. elegans link the increase in H3K27me3 levels to increased longevity.

In contrast, in Drosophila, an increase in longevity was coupled to a decrease in H3K27me3 levels [27]. H3K27me3 is classically deposited and maintained by the Polycomb complexes. Polycomb repressive complex-2 (PRC2) contains one of the methyltransferases, enhancer of zeste homolog-1 or -2 (EZH1 or EZH2, respectively) [22]. Mutation of the Drosophila’s homologue of EZH1/2, E(Z), as well as mutation of its H3-targeting partner protein ESC, led to the decrease in H3K27me3 levels and concomitant increase in longevity [27]. Consistently, Graffman et al. reported the increase in the expression of a Polycomb protein EED and increase of H3K27me3 levels in human early hematopoietic progenitors with age [28]. Recent meta-analysis of ENCODE and Roadmap Epigenomics data further supports the increase in H3K27me3 levels during ageing by showing the increase in Polycomb proteins and H3K27me3 in age-associated genomic regions [29]. Additionally, in Drosophila, mutations to known Polycomb’s antagonist Trithorax group proteins restored the H3K27me3 levels and abolished the increase in longevity [27].

The discrepancy between H3K27me3 levels and longevity between C. elegans and other models might be the result of inter-species differences. Also, different components of the H3K27me3-maintenance system were investigated in these studies. Differing targets of these maintenance systems, besides H3K27, might contribute to lifespan regulation and account for the differences observed. EZH2, the Polycomb’s H3K27me3 methyltransferase, was reported to act independently from PRC2 complex in cancer cells [30]. Furthermore, the cross-talk between H3K27me3 methyltransferases/demethylases and other regulators could help to explain the interspecies differences. For instance, the SIRT1 deacetylase was shown to affect the methylation status of Polycomb target genes [31].

Finally, it is not the global levels of histone marks, but rather their localization and regulation of specific groups of genes, that plays a functional role in the regulation of cellular fate. Recent findings showed that the expression of Polycomb’s Ezh1, Ezh2, and Cbx2, and of its co-regulators Aurka and Aurkb, decreased with ageing in murine hematopoietic stem cells (HSCs) [32••]. This was accompanied by redistribution of the ChIP-seq-profiled H3K27me3, whose total peak counts did not change, but whose abundance decreased at certain promoters to increase at others [32••].


H3K4me3 histone mark is the most abundant in close proximity of transcription start sites (TSSs) [33]. It is associated with, though not indispensable for, active transcription [34]. H3K4me3 is also present along with the repressive H3K27me3 mark in so-called bivalent domains that associate with developmentally important genes, allowing them to be activated or repressed as the differentiation proceeds [35].

High H3K4me3 levels seem to promote ageing, as its disruption leads to increase in lifespan: knockdown of each of the H3K4me3 methyltrasferases ASH-2, WDR5, and SET-2 in C. elegans led to decrease in H3K4me3 levels and concomitant increase in lifespan [36]. Consistently, knockdown or inhibition of H3K4me3 demethylases caused an increase in H3K4me3 levels and a decrease in the lifespan of C. elegans and Drosophila [36, 37, 38, 39].

Another argument for the functional role of H3K4me3 in promoting ageing is its correlation with gene expression. Sun et al. reported a significant increase of H4K4me3 levels at 267 gene promoters in aged hematopoietic stem cells (HSCs), which overall positively correlated with gene expression [32••]. This was accompanied by a loss of H3K4me3 at 73 promoters, which suggests that not only global levels but also the localization of H3K4me3 to specific genes is important. Consistent with this notion, besides the increase in the number of H3K4me3 ChIP-seq peaks with age, Sun et al. reported concomitant increase in the breadth of ~50 % of the H3K4me3 peaks [32••]. These broadened peaks tended to associate with genes that determine HSC identity, consistently with the recent findings that the broadest H3K4me3 domains control the cell-identity-related genes by increasing their transcriptional consistency [40•].


H3K36me3, similarly to H3K4me3, is associated with active transcription but located in gene bodies rather than at promoters [41]. It plays a role in sustaining transcriptional elongation by RNA polymerase II and preventing cryptic transcription [42, 43••, 44]. Only very recently has the H3K36me3 mark been associated with regulation of ageing.

A histone mutant screen in Saccharomyces cerevisiae revealed H3K36me3 as a mark responsible for lifespan regulation [43••]. Different amino acid substitutions of H3K36 all resulted in shortened lifespan, and deletion of the H3K36 demethylase, Rph1, increased the H3K36me3 levels and extended lifespan of wild type yeast, but not H3K36 mutant yeast, showing that indeed the presence of the methylation at H3K36 is required for the lifespan extension [43••]. The age-dependent loss of H3K36me3 at specific loci associated with emergence of cryptic transcription in ageing yeast, a phenomenon that also occurred in aged C. elegans, suggesting that H3K36me3-mediated regulation of ageing might be conserved from yeast to worms [43••].

Indeed, another recent study confirmed that H3K36me3 is required for regulation of lifespan in C. elegans [45•]. Interference with the met-1 methyltransferase resulted in decreased H3K36me3 levels and shortened lifespan [45•]. While no obvious age-dependent changes occurred in the distribution of H3K36me3, there was a negative correlation between the initial H3K36me3 levels and the change in gene expression upon ageing, once more suggesting a role for H3K36me3 in maintaining transcriptional consistency [45•]. Additional analysis of data from Drosophila melanogaster revealed similar correlation between H3K36me3 and age-dependent transcriptional changes, further supporting the conserved nature of H3K36me3-mediated regulation in ageing [21, 45•].


The acetylation of lysine 56 on histone H3 (H3K56ac) is evolutionarily conserved from yeast to man [46]. In S. cerevisiae, it promotes de novo nucleosome assembly, genomic stability, transcription, and formation of heterochromatin/euchromatin boundaries [47, 48, 49, 50, 51, 52]. In mammals, the role of H3K56ac remains elusive, but recent evidence indicates that it also promotes genomic stability [46].

H3K56 can be deacetylated by a variety of NAD+-dependent deacetylases collectively known as Sirtuins. In yeast, the Sirtuin proteins Hst3, Hst4, and Sir2 deacetylate H3K56, while in mammals, the Sir2 orthologues Sirt1, Sirt2, Sirt3, and Sirt6 carry out this reaction [46, 53, 54, 55]. Importantly, the activity of Sirtuin proteins has been strongly linked to increased lifespan [56]. Indeed, Sir2 levels are known to decrease in yeast with increasing age [57]. Furthermore, deletions of Sir2, Hst3, and Hst4 shorten lifespan in yeast, while overexpression of Sir2 lengthens it [57, 58].

The Sir2-mediated lifespan extension in yeast appears to work through the maintenance of genomic integrity of ribosomal DNA (rDNA) [59]. In yeast, the rDNA is thought to play a very important role in lifespan regulation, but mutations that abolish H3K56ac do not mimic the effects of Sir2 overexpression, suggesting that the H3K56ac levels at rDNA are not the sole regulator of lifespan [58, 60]. However, mutations in rtt109 and asf result in hyperamplification of rDNA repeats, which has been linked to decreased lifespan [61, 62]. In accordance with this, an H3K56R mutant that mimics a constitutively unacetylated H3K56 also displays rDNA hyperamplification and is short-lived [57, 61]. Paradoxically, also an H3K56 acetyl-mimic (H3K56Q) led to increased hyperamplification of rDNA and decrease in lifespan [57, 61]. This suggests that the right balance of H3K56 acetylation is required to maintain cellular function. Nonetheless, H3K56ac levels have been shown to decrease in yeast with increasing age, and it was recently shown in yeast that the downregulation of ribosome biogenesis by TOR signaling, known to be a conserved mechanism for lifespan extension in many organisms, is partly mediated by the downregulation of H3K56ac specifically at the rDNA [63]. These contradictory data make it difficult to determine the degree of involvement of H3K56ac in regulating lifespan in yeast. In mammals, the role of H3K56ac in lifespan extension remains to be investigated.


H4K16ac is another histone target of sirtuin deacetylases. In yeast, the opposing activities of sir2 deacetylase and Sas2 acetyltransferase establish an H4K16ac gradient in close proximity of telomeres. This gradient defines a heterochromatin/euchromatin boundary and functions to promote transcription by preventing the spreading of telomeric heterochromatin [64, 65]. In Drosophila, hyper-acetylation of H4K16 on chromosome X is required for upregulation of gene expression during dosage compensation and the general transcriptional program. Next to its role in transcription, in mammals, H4K16ac is also involved in promoting DNA repair [66, 67].

In yeast, levels of H4K16ac, unlike H3K56ac, increase during ageing [57]. This might be due to the age-related decrease in sir2 [57]. However, as seen with H3K56ac, mutations of H4K16 that mimic its constitutively acetylated and unacetylated forms (H4K16Q and H4K16R, respectively) both result in a reduction of lifespan [57].

In mammals, a study of an in vitro progeria mouse model, which displays a premature ageing phenotype, showed that H4K16 was hypoacetylated in Zmpste-24-null fibroblasts due to a mutant prelamin A (progerin)-mediated mislocalization of the H4K16 acetyltransferase MOF [68]. This was shown to result in deficient recruitment of DNA repair factors to DNA damage. Knockdown of Mof in late passage wild-type mouse fibroblasts resulted in a decrease in H4K16ac and an increase in cellular senescence, recapitulating what was observed in the progeria model of Zmpste-24-null fibroblasts [68]. Furthermore, Zmpste-24-null mice whose diets were supplemented with histone deacetylase inhibitors demonstrated a small but significant extension of lifespan [68]. These data suggest that part of the accelerated ageing phenotype observed in progeria syndromes could be a direct consequence of reduced H4K16ac. However, further studies would be needed to clarify the exact extent to which H4K16ac prevents the accelerated ageing seen in progeria syndromes.

H2B monoubiquitylation

Another active mark, histone H2B monoubiquitylation (H2Bub), is required for the trimethylation of H3K4 and H3K79, a role which seems to be conserved between species [69, 70, 71, 72, 73, 74]. This suggests that H2Bub could indirectly affect ageing through regulation of H3K4me3 levels.

Indeed, the role of H2Bub itself in the regulation of lifespan has recently been shown in yeast [75]. H2Bub accumulated in heterochromatic regions during cellular ageing, accompanied by an increase in H3K4me3, H3K79me3, and H4K16ac [75]. Disruption of H2B ubiquitylation led to a reduction in yeast lifespan; however, it had no additional effect over a Sir2 mutant, suggesting that the role of H2Bub in yeast ageing might be coupled to the Sir2-H4K16ac axis described above, rather than to H3K4me3 regulation [75].

Potential Role of Other Histone Modifications in the Regulation of Ageing

Up to this point, we have described histone modifications that have already been implicated to influence ageing (see sections above). Intriguingly, a recent screen using a yeast histone mutant library implies that many more histone modifications might regulate lifespan, as summarized in Table 1 [43••]. Of 38 uniquely mutated sites within histones H3 and H4 that change lifespan by over 20 %, 15 sites are residues previously reported to be post-translationally modified. It is tempting to speculate that the identified mutations point toward so far unknown ageing-related histone modifications and thus might prove useful as a resource for researchers interested in the involvement of epigenetics in ageing. Mutations of the majority of the 38 newly identified sites decrease lifespan. Nevertheless, six of the mutations increase yeast lifespan over 25 %. These are K14Q, K64A, K115A, K122A, and R128A in histone H3, and K77A in histone H4.
Table 1

Novel histone modification sites with putative function in ageing and lifespan regulation











Transcription, repair

[76, 77]





[78, 79]














Transcription, replication, repair

[47, 48, 49]




Transcription, silencing





































[88, 89]











Lifespan reported if changes are greater than 20 %

PTM post-translational modification

H3R128 was shown to be methylated in brains of a 12-month-old progeria model mice [86]. However, it remains to be seen whether its levels are affected over the course of the organismal lifespan. Furthermore, the function of this modification is unknown to date. H4K77 is the site of acetylation and ubiquitination [91]. It has been demonstrated at least in vitro that acetylation of H4K77 enhances the instability of nucleosomes, an effect that can also be observed in ageing yeast cells [92]. H3K64, 155, and 122 all map to the lateral surface of the nucleosome where the DNA-protein interaction is at its maximum strength [93]. All three residues can also be acetylated, and this weakens histone-DNA contacts [85, 94, 95]. Interestingly, H3K64 can also be tri-methylated, a modification that localizes to repressive chromatin [81]. It would be highly interesting to investigate how this interplay between methylation and acetylation would change with age. Finally, H3K14Q is the only lifespan-extending mutation that harbors the acetylation-mimicking glutamine, while the unmodifiable mimic arginine does not alter lifespan. This is particularly interesting as H3K14 acetylation has been correlated with the regulation of stress response genes and the induction and coordination of the DNA damage response pathways that are well known to enhance lifespan [76, 77, 96, 97, 98].

Besides the novel targets revealed in the screen, there are two classes of important protein modifications, arginine methylation and GlcNAcylation, that have been associated with ageing and lifespan regulation; however, it remains unclear if their effects depend on epigenetic mechanisms [99, 100, 101, 102, 103].

Arginine residues can be methylated by enzymes that belong to the mammalian protein arginine methyltransferases (PRMTs) or to its homologous Drosophila arginine methyltransferases (DARTs) [104, 105]. PRMTs were reported to change their expression in an age-dependent manner in rat tissues [99]. Interestingly, PRMT6−/− MEF cells exhibited a senescence-like phenotype, associated with decreased levels of H3R2 methylation, a modification suggested to be involved in the maintenance of euchromatin [100]. However, as PRMTs methylate a variety of target proteins, it remains to be seen whether histone-arginine methylation is involved in regulation of ageing.

The target proteins of O-GlcNAcylation are also diverse, ranging from signaling pathway mediators to epigenetic regulators [106]. However, all core histones can be modified with O-GlcNAc [106, 107, 108, 109, 110, 111].

Using anti-GlcNAc antibody, Love et al. identified over 800 genes, whose promoters were enriched in GlcNAc-modified proteins in C. elegans [102]. GlcNAcylation localized in proximity of promoters of genes associated with ageing, among other processes [102]. GlcNAcylation is carried out by O-GlcNAc transferase (OGT), while its removal by O-GlcNAcase (OGA) [106]. Deletion of ogt-1 led to decrease in lifespan, while deletion of oga-1 to increase in lifespan in C. elegans [102, 103]. This effect of the GlcNAc cycling enzymes seemed to be at least partly dependent on the insulin-signaling pathway and its downstream DAF16/FOXO transcription factor, a known regulator of ageing in C. elegans and other organisms [102, 103]. As Love et al. investigated DNA-associated protein GlcNAcylation, it seems plausible that the modification was present, among others, at histone proteins. Along with other modifications described in this section, it will be highly interesting to see whether and how GlcNacylation of histones plays a role in regulation of organismal lifespan. However, the detectability, and hence the existence, of histone GlcNAcylation in mammalian cells are currently under dispute, questioning its putative role in ageing in higher organisms [112].


Along with the investigation of novel histone marks in ageing, the challenge for the field will be the integration of the information on single histone marks, to better understand their interplay. A well-known example of interaction between two histone marks occurs in bivalent domains that contain both active H3K4me3 and repressive H3K27me3. As described by Sun et al., in aged HSCs, 355 bivalent domains were lost and 1245 were gained, either through gain in both H3K4me3 and H3K27me3, or only in H3K27me3 [32••]. This suggests that monitoring of single histone marks in ageing, while important, may only yield partial information. Knowledge of the individual functions of modifications as well as of their interplay will be crucial for complete understanding of their role in ageing. Furthermore, it might be important to put less stress on monitoring the global levels of modifications and pay more attention to their redistribution patterns towards different sets of genomic regions during ageing.

A next step forward should be further integration of the data on histone modifications with data on DNA methylation, cellular signaling, and metabolism. The most recent reports seem to weigh in this direction, raising hopes for development of a complete, systems biology model that would integrate epigenetic, genetic, metabolic, and signaling mechanisms of ageing [17, 32••, 113•].

While integrative approaches will most likely gain in importance in the coming years, thanks to increasing computational expertise and computational power in the field, another challenge will be to uncouple the likely different epigenetic mechanisms of ageing in different tissues or even cell types. Current approaches often still focus on a specific tissue, if not a whole organ. However, the epigenetic patterns of histone modifications vary greatly between specific cell types. The bivalent domains mentioned above, or the enhancers, present a drastically different make-up in different cell types. This suggests that also the changes acquired during ageing might be of different nature. Profiling of whole organs or tissues, although important, might only monitor the average of the cell populations within the organ and thus miss subtle, cell type-specific changes. While it seems obvious in mammals, it is also important in small model organisms: Pu et al. and others used germlineless worms in their ageing research, because of the dramatic changes that occur in the germline during adulthood, which could mask the somatic epigenetic changes [45•]. Therefore, it will be of high importance in the coming years to investigate the mechanisms of ageing in specific, selected cellular populations.

While methods are in place to achieve the population-level cellular resolution, e.g., fluorescence-activated cell sorting (FACS), there remains a challenge of working with very low cell numbers those populations might consist of. Traditionally, many methods, especially ChIP, required very high inputs. Methods have now been developed to perform DNA methylation, RNA-seq, and even ChIP-seq experiments with cellular inputs reaching down to a single cell, accompanied by development of computational approaches and tools enabling the analysis [114, 115, 116, 117, 118, 119, 120]. The establishment of the single-cell techniques will also permit the next step forward: investigating the dynamics of epigenetic modifications of single cells in seemingly uniform cellular populations [114, 119].


The research of recent years has established links between histone modifications and ageing or lifespan regulation. However, the pool of histone mark candidates involved in ageing is growing and future investigation of the new ageing-associated histone marks, as well as integration of epigenetic data with other areas of cellular activity, will be important to reveal a systems biology mechanism of ageing.

The current understanding of the role that the changes in histone modifications play in ageing is not complete. In many cases, conflicting reports are present in regard to the presence or direction of change in the levels of particular histone marks during ageing. However, their functional role in promoting or restraining longevity is often clearly indicated by studies in mutant models.

It seems that the net changes in amounts of specific histone marks are not as important as their localization. It is rather the redistribution of marks and reorganization of chromatin that may regulate ageing (Fig. 1). Histone modifications are reshuffled to control different sets of genes. This redistribution of modifications, and their net effect on transcription of specific sets of genes, is therefore the most likely explanation for the impact of histone marks on ageing.
Fig. 1

Redistribution of histone modifications during ageing. Simplified representations of: a a chromosome, illustrating how changes in histone modifications (represented by different colors) may occur during ageing, with or without affecting the global levels of the modifications. Such age-dependent alterations in chromatin structure might affect DNA-templated processes resulting in the ageing phenotype; b a single, ageing-associated locus in which ageing-related changes in histone modifications occur. Modification 1 (blue) is lost upon ageing, while modification 2 (green) becomes enriched. Even if the levels of modification 3 (red) remain the same, the new epigenetic state due to changes in modifications 1 and 2 will likely alter DNA-templated processes occurring in this genomic region, contributing to ageing phenotype. The peaks represent putative ChIP-seq profiles



Work in our laboratory is funded by the Max Planck Society.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Simboeck E, Ribeiro JD, Teichmann S, Di Croce L. Epigenetics and senescence: learning from the INK4-ARF locus. Biochem Pharmacol. 2011;82:1361–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Benayoun BA, Pollina EA, Brunet A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol. 2015;16:593–610.PubMedCrossRefGoogle Scholar
  3. 3.
    Hall JA, Dominy JE, Lee Y, Puigserver P. The sirtuin family's role in aging and age-associated pathologies. J Clin Invest. 2013;123:973–9.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Jung M, Pfeifer GP. Aging and DNA methylation. BMC Biol. 2015;13:7.PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Bürkle A, Caiafa P. Reconfiguration of DNA methylation in aging. Mech Ageing Dev. 2015;151:60–70.PubMedCrossRefGoogle Scholar
  6. 6.
    Saksouk N, Simboeck E, Déjardin J. Constitutive heterochromatin formation and transcription in mammals. Epigenetics Chromatin. 2015;8:3.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, et al. Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3-K9. Genes Dev. 2005;19:815–26.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Rai K, Jafri IF, Chidester S, James SR, Karpf AR, Cairns BR, et al. Dnmt3 and G9a cooperate for tissue-specific development in zebrafish. J Biol Chem. 2010;285:4110–21.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Zylicz JJ, Dietmann S, Günesdogan U, Hackett JA, Cougot D, Lee C, et al. Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development. eLife. 2015;4Google Scholar
  10. 10.
    Lachner M, O'Carroll D, Rea S, Mechtler K, Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001;410:116–20.PubMedCrossRefGoogle Scholar
  11. 11.
    Bannister AJ, Zegerman P, Partridge JF, Miska EA. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001;410:120–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Eissenberg JC, Elgin SCR. HP1a: a structural chromosomal protein regulating transcription. Trends Genet. 2014;30:103–10.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Tsurumi A, Li WX. Global heterochromatin loss: a unifying theory of aging? Epigenetics. 2012;7:680–8.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Villeponteau B. The heterochromatin loss model of aging. Exp Gerontol. 1997;32:383–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Haithcock E, Dayani Y, Neufeld E, Zahand AJ, Feinstein N, Mattout A, et al. Age-related changes of nuclear architecture in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2005;102:16690–5.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Larson K, Yan S-J, Tsurumi A, Liu J, Zhou J, Gaur K, et al. Heterochromatin formation promotes longevity and represses ribosomal RNA synthesis. PLoS Genet. 2012;8:e1002473.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, et al. Aging stem cells. a Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science. 2015;348:1160–3.PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Shumaker DK, Dechat T, Kohlmaier A, Adam SA, Bozovsky MR, Erdos MR, et al. Mutant nuclear lamin a leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A. 2006;103:8703–8.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Liu B, Wang Z, Zhang L, Ghosh S, Zheng H, Zhou Z. Depleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model. Nat Commun. 2013;4:1868.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Ni Z, Ebata A, Alipanahiramandi E, Lee SS. Two SET domain containing genes link epigenetic changes and aging in Caenorhabditis elegans. Aging Cell. 2012;11:315–25.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Wood JG, Hillenmeyer S, Lawrence C, Chang C, Hosier S, Lightfoot W, et al. Chromatin remodeling in the aging genome of Drosophila. Aging Cell. 2010;9:971–8.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Bracken AP, Helin K. Polycomb group proteins: navigators of lineage pathways led astray in cancer. Nat Rev Cancer. 2009;9:773–84.PubMedCrossRefGoogle Scholar
  23. 23.
    Maures TJ, Greer EL, Hauswirth AG, Brunet A. The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell. 2011;10:980–90.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Jin C, Li J, Green CD, Yu X, Tang X, Han D, et al. Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway. Cell Metab. 2011;14:161–72.PubMedCrossRefGoogle Scholar
  25. 25.
    Agger K, Cloos PAC, Rudkjaer L, Williams K, Andersen G, Christensen J, et al. The H3K27me3 demethylase JMJD3 contributes to the activation of the INK4A-ARF locus in response to oncogene- and stress-induced senescence. Genes Dev. 2009;23:1171–6.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Barradas M, Anderton E, Acosta JC, Li S, Banito A, Rodriguez-Niedenführ M, et al. Histone demethylase JMJD3 contributes to epigenetic control of INK4a/ARF by oncogenic RAS. Genes Dev. 2009;23:1177–82.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Siebold AP, Banerjee R, Tie F, Kiss DL, Moskowitz J, Harte PJ. Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance. Proc Natl Acad Sci U S A. 2010;107:169–74.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Graffmann N, Brands J, Görgens A, Vitoriano da Conceição Castro S, Santourlidis S, Reckert A, et al. Age-Related Increase of EED Expression in Early Hematopoietic Progenitor Cells is Associated with Global Increase of the Histone Modification H3K27me3. Stem Cells and Dev. 2015;24:2018–31.CrossRefGoogle Scholar
  29. 29.
    Dozmorov MG. Polycomb repressive complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes. Epigenetics. 2015;10:484–95.PubMedCrossRefGoogle Scholar
  30. 30.
    Xu K, Wu ZJ, Groner AC, He HH, Cai C, Lis RT, et al. EZH2 oncogenic activity in castration-resistant prostate cancer cells is Polycomb-independent. Science. 2012;338:1465–9.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Wakeling LA, Ions LJ, Escolme SM, Cockell SJ, Su T, Dey M, et al. SIRT1 affects DNA methylation of polycomb group protein target genes, a hotspot of the epigenetic shift observed in ageing. Hum Genomics. 2015;9:14.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.••
    Sun D, Luo M, Jeong M, Rodriguez B, Xia Z, Hannah R, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14:673–88. One of the first studies integrating the information on multiple histone modifications and transcriptomic profiles in ageing. They explored how H3K4me3, H3K27me3 and H3K36me3 levels redistribute in ageing HSCs. PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Santos-Rosa H, Schneider R, Bannister AJ, Sherriff J, Bernstein BE, Emre NCT, et al. Active genes are tri-methylated at K4 of histone H3. Nature. 2002;419:407–11.PubMedCrossRefGoogle Scholar
  34. 34.
    Hödl M, Basler K. Transcription in the absence of histone H3.2 and H3K4 methylation. Curr Biol. 2012;22:2253–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–26.PubMedCrossRefGoogle Scholar
  36. 36.
    Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, et al. Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature. 2010;466:383–7.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Alvares SM, Mayberry GA, Joyner EY, Lakowski B, Ahmed S. H3K4 demethylase activities repress proliferative and postmitotic aging. Aging Cell. 2014;13:245–53.PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    McColl G, Killilea DW, Hubbard AE, Vantipalli MC, Melov S, Lithgow GJ. Pharmacogenetic analysis of lithium-induced delayed aging in Caenorhabditis elegans. J Biol Chem. 2008;283:350–7.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Li L, Greer C, Eisenman RN, Secombe J. Essential functions of the histone demethylase lid. PLoS Genet. 2010;6:e1001221.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.•
    Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong ED, et al. H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell. 2014;158:673–88. An interesting study using bioinformatical approaches to distinguish the function of broad H3K4me3 domains, which implied their role in preserving transcriptional consistency at cell identity-related genes. PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Bannister AJ, Schneider R, Myers FA, Thorne AW, Crane-Robinson C, Kouzarides T. Spatial distribution of di- and tri-methyl lysine 36 of histone H3 at active genes. J Biol Chem. 2005;280:17732–6.PubMedCrossRefGoogle Scholar
  42. 42.
    Carrozza MJ, Li B, Florens L, Suganuma T, Swanson SK, Lee KK, et al. Histone H3 methylation by Set2 directs deacetylation of coding regions by Rpd3S to suppress spurious intragenic transcription. Cell. 2005;123:581–92.PubMedCrossRefGoogle Scholar
  43. 43.••
    Sen P, Dang W, Donahue G, Dai J, Dorsey J, Cao X, et al. H3K36 methylation promotes longevity by enhancing transcriptional fidelity. Genes Dev. 2015;29:1362–76. First study to report a large screen of yeast histone mutant library in regard to the lifespan. The study provides an important resource – multiple candidate histone modification sites – for researchers interested in epigenetics of ageing and longevity. PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Venkatesh S, Smolle M, Li H, Gogol MM, Saint M, Kumar S, et al. Set2 methylation of histone H3 lysine 36 suppresses histone exchange on transcribed genes. Nature. 2012;489:452–5.PubMedCrossRefGoogle Scholar
  45. 45.•
    Pu M, Ni Z, Wang M, Wang X, Wood JG, Helfand SL, et al. Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span. Genes Dev. 2015;29:718–31. This study reported the role of H3K36me3 in the regulation of lifespan in C. elegans, in the same time when Sen et al. proposed it in yeast. PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    Yuan J, Pu M, Zhang Z, Lou Z. Histone H3-K56 acetylation is important for genomic stability in mammals. Cell Cycle. 2009;8:1747–53.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Rufiange A, Jacques P-É, Bhat W, Robert F, Nourani A. Genome-wide replication-independent histone H3 exchange occurs predominantly at promoters and implicates H3 K56 acetylation and Asf1. Mol Cell. 2007;27:393–405.PubMedCrossRefGoogle Scholar
  48. 48.
    Li Q, Zhou H, Wurtele H, Davies B, Horazdovsky B, Verreault A, et al. Acetylation of histone H3 lysine 56 regulates replication-coupled nucleosome assembly. Cell. 2008;134:244–55.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Masumoto H, Hawke D, Kobayashi R, Verreault A. A role for cell-cycle-regulated histone H3 lysine 56 acetylation in the DNA damage response. Nature. 2005;436:294–8.PubMedCrossRefGoogle Scholar
  50. 50.
    Driscoll R, Hudson A, Jackson SP. Yeast Rtt109 promotes genome stability by acetylating histone H3 on lysine 56. Science. 2007;315:649–52.PubMedCentralPubMedCrossRefGoogle Scholar
  51. 51.
    Han J, Zhou H, Horazdovsky B, Zhang K, Xu R-M, Zhang Z. Rtt109 acetylates histone H3 lysine 56 and functions in DNA replication. Science. 2007;315:653–5.PubMedCrossRefGoogle Scholar
  52. 52.
    Lu PYT, Kobor MS. Maintenance of Heterochromatin Boundary and Nucleosome Composition at Promoters by the Asf1 Histone Chaperone and SWR1-C Chromatin Remodeler in Saccharomyces cerevisiae. Genetics Genetics Society of America. 2014;197:133–45.Google Scholar
  53. 53.
    Celic I, Masumoto H, Griffith WP, Meluh P, Cotter RJ, Boeke JD, et al. The sirtuins hst3 and Hst4p preserve genome integrity by controlling histone h3 lysine 56 deacetylation. Curr Biol. 2006;16:1280–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Michishita E, McCord RA, Boxer LD, Barber MF, Hong T, Gozani O, et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009;8:2664–6.PubMedCentralPubMedCrossRefGoogle Scholar
  55. 55.
    Vempati RK, Jayani RS, Notani D, Sengupta A, Galande S, Haldar D. p300-mediated acetylation of histone H3 lysine 56 functions in DNA damage response in mammals. J Biol Chem. 2010;285:28553–64.PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Giblin W, Skinner ME, Lombard DB. Sirtuins: guardians of mammalian healthspan. Trends Genet. 2014;30:271–86.PubMedCentralPubMedCrossRefGoogle Scholar
  57. 57.
    Dang W, Steffen KK, Perry R, Dorsey JA, Johnson FB, Shilatifard A, et al. Histone H4 lysine 16 acetylation regulates cellular lifespan. Nature. 2009;459:802–7.PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 1999;13:2570–80.PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Saka K, Ide S, Ganley ARD, Kobayashi T. Cellular senescence in yeast is regulated by rDNA noncoding transcription. Curr Biol. 2013;23:1794–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Ganley ARD, Kobayashi T. Ribosomal DNA and cellular senescence: new evidence supporting the connection between rDNA and aging. FEMS Yeast Res. 2014;14:49–59.PubMedCrossRefGoogle Scholar
  61. 61.
    Ide S, Saka K, Kobayashi T. Rtt109 prevents hyper-amplification of ribosomal RNA genes through histone modification in budding yeast. PLoS Genet. 2013;9:e1003410.PubMedCentralPubMedCrossRefGoogle Scholar
  62. 62.
    Houseley J, Tollervey D. Repeat expansion in the budding yeast ribosomal DNA can occur independently of the canonical homologous recombination machinery. Nucleic Acids Res. 2011;39:8778–91.PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Chen H, Fan M, Pfeffer LM, Laribee RN. The histone H3 lysine 56 acetylation pathway is regulated by target of rapamycin (TOR) signaling and functions directly in ribosomal RNA biogenesis. Nucleic Acids Res. 2012;40:6534–46.PubMedCentralPubMedCrossRefGoogle Scholar
  64. 64.
    Kimura A, Umehara T, Horikoshi M. Chromosomal gradient of histone acetylation established by Sas2p and Sir2p functions as a shield against gene silencing. Nat Genet. 2002;32:370–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Suka N, Luo K, Grunstein M. Sir2p and Sas2p opposingly regulate acetylation of yeast histone H4 lysine16 and spreading of heterochromatin. Nat Genet. 2002;32:378–83.PubMedCrossRefGoogle Scholar
  66. 66.
    Conrad T, Akhtar A. Dosage compensation in Drosophila melanogaster: epigenetic fine-tuning of chromosome-wide transcription. Nature Rev Genet. 2011;13:123–34.CrossRefGoogle Scholar
  67. 67.
    Sharma GG, So S, Gupta A, Kumar R, Cayrou C, Avvakumov N, et al. MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair. Mol Cell Biol. 2010;30:3582–95.PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Krishnan V, Chow MZY, Wang Z, Zhang L, Liu B, Liu X, et al. Histone H4 lysine 16 hypoacetylation is associated with defective DNA repair and premature senescence in Zmpste24-deficient mice. Proc Natl Acad Sci U S A. 2011;108:12325–30.PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis. Annu Rev Biochem. 2012;81:65–95.PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Lee J-S, Shukla A, Schneider J, Swanson SK, Washburn MP, Florens L, et al. Histone crosstalk between H2B monoubiquitination and H3 methylation mediated by COMPASS. Cell. 2007;131:1084–96.PubMedCrossRefGoogle Scholar
  71. 71.
    Wu L, Lee SY, Zhou B, Nguyen UTT, Muir TW, Tan S, et al. ASH2L regulates ubiquitylation signaling to MLL: trans-regulation of H3 K4 methylation in higher eukaryotes. Mol Cell. 2013;49:1108–20.PubMedCentralPubMedCrossRefGoogle Scholar
  72. 72.
    Kim J, Guermah M, McGinty RK, Lee J-S, Tang Z, Milne TA, et al. RAD6-Mediated transcription-coupled H2B ubiquitylation directly stimulates H3K4 methylation in human cells. Cell. 2009;137:459–71.PubMedCentralPubMedCrossRefGoogle Scholar
  73. 73.
    McGinty RK, Kim J, Chatterjee C, Roeder RG, Muir TW. Chemically ubiquitylated histone H2B stimulates hDot1L-mediated intranucleosomal methylation. Nature. 2008;453:812–6.PubMedCentralPubMedCrossRefGoogle Scholar
  74. 74.
    Jung I, Kim S-K, Kim M, Han Y-M, Kim YS, Kim D, et al. H2B monoubiquitylation is a 5'-enriched active transcription mark and correlates with exon-intron structure in human cells. Genome Res. 2012;22:1026–35.PubMedCentralPubMedCrossRefGoogle Scholar
  75. 75.
    Rhie B-H, Song Y-H, Ryu H-Y, Ahn SH. Cellular aging is associated with increased ubiquitylation of histone H2B in yeast telomeric heterochromatin. Biochem Biophys Res Commun. 2013;439:570–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Johnsson A, Durand-Dubief M, Xue-Franzén Y, Rönnerblad M, Ekwall K, Wright A. HAT-HDAC interplay modulates global histone H3K14 acetylation in gene-coding regions during stress. EMBO Rep. 2009;10:1009–14.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Duan M-R, Smerdon MJ. Histone H3 lysine 14 (H3K14) acetylation facilitates DNA repair in a positioned nucleosome by stabilizing the binding of the chromatin Remodeler RSC (Remodels Structure of Chromatin). J Biol Chem. 2014;289:8353–63.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Zee BM, Levin RS, Xu B, LeRoy G, Wingreen NS, Garcia BA. In vivo residue-specific histone methylation dynamics. J Biol Chem. 2010;285:3341–50.PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Seligson DB, Horvath S, Shi T, Yu H, Tze S, Grunstein M, et al. Global histone modification patterns predict risk of prostate cancer recurrence. Nature. 2005;435:1262–6.PubMedCrossRefGoogle Scholar
  80. 80.
    Hyland EM, Molina H, Poorey K, Jie C, Xie Z, Dai J, et al. An evolutionarily “young” lysine residue in histone H3 attenuates transcriptional output in Saccharomyces cerevisiae. Genes Dev. 2011;25:1306–19.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Daujat S, Weiss T, Mohn F, Lange UC, Ziegler-Birling C, Zeissler U, et al. H3K64 trimethylation marks heterochromatin and is dynamically remodeled during developmental reprogramming. Nat Struct Mol Biol. 2009;16:777–81.PubMedCrossRefGoogle Scholar
  82. 82.
    van Leeuwen F, Gafken PR, Gottschling DE. Dot1p modulates silencing in yeast by methylation of the nucleosome core. Cell. 2002;109:745–56.PubMedCrossRefGoogle Scholar
  83. 83.
    Hammond SL, Byrum SD, Namjoshi S, Graves HK, Dennehey BK, Tackett AJ, et al. Mitotic phosphorylation of histone H3 threonine 80. Cell Cycle. 2014;13:440–52.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell. 2011;146:1016–28.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Tropberger P, Pott S, Keller C, Kamieniarz-Gdula K, Caron M, Richter F, et al. Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell. 2013;152:859–72.PubMedCrossRefGoogle Scholar
  86. 86.
    Wang CM, Tsai SN, Yew TW, Kwan YW, Ngai SM. Identification of histone methylation multiplicities patterns in the brain of senescence-accelerated prone mouse 8. Biogerontology. 2010;11:87–102.PubMedCrossRefGoogle Scholar
  87. 87.
    Fingerman IM, Li H-C, Briggs SD. A charge-based interaction between histone H4 and Dot1 is required for H3K79 methylation and telomere silencing: identification of a new trans-histone pathway. Genes Dev. 2007;21:2018–29.PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Kim K, Lee B, Kim J, Choi J, Kim J-M, Xiong Y, et al. Linker Histone H1.2 cooperates with Cul4A and PAF1 to drive H4K31 ubiquitylation-mediated transactivation. Cell Rep. 2013;5:1690–703.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Beck HC, Nielsen EC, Matthiesen R, Jensen LH, Sehested M, Finn P, et al. Quantitative proteomic analysis of post-translational modifications of human histones. Mol Cell Proteomics. 2006;5:1314–25.PubMedCrossRefGoogle Scholar
  90. 90.
    Hu J, Donahue G, Dorsey J, Govin J, Yuan Z, Garcia BA, et al. H4K44 Acetylation facilitates chromatin accessibility during Meiosis. Cell Rep. 2015;13:1772–80.PubMedCrossRefGoogle Scholar
  91. 91.
    Wu Q, Cheng Z, Zhu J, Xu W, Peng X, Chen C, et al. Suberoylanilide hydroxamic acid treatment reveals crosstalks among proteome, ubiquitylome and acetylome in non-small cell lung cancer A549 cell line. Sci Rep. 2015;5:9520.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Simon M, North JA, Shimko JC, Forties RA, Ferdinand MB, Manohar M, et al. Histone fold modifications control nucleosome unwrapping and disassembly. Proc Natl Acad Sci U S A. 2011;108:12711–6.PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Hall MA, Shundrovsky A, Bai L, Fulbright RM, Lis JT, Wang MD. High-resolution dynamic mapping of histone-DNA interactions in a nucleosome. Nat Struct Mol Biol. 2009;16:124–9.PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Tropberger P, Schneider R. Going global Novel histone modifications in the globular domain of H3. Epigenetics. 2010;5:112–7.PubMedCrossRefGoogle Scholar
  95. 95.
    Di Cerbo V, Mohn F, Ryan DP, Montellier E, Kacem S, Tropberger P, et al. Acetylation of histone H3 at lysine 64 regulates nucleosome dynamics and facilitates transcription. eLife. 2014;3:e01632.PubMedCentralPubMedCrossRefGoogle Scholar
  96. 96.
    Huisinga KL, Pugh BF. A genome-wide housekeeping role for TFIID and a highly regulated stress-related role for SAGA in Saccharomyces cerevisiae. Mol Cell. 2004;13:573–85.PubMedCrossRefGoogle Scholar
  97. 97.
    Wang Y, Kallgren SP, Reddy BD, Kuntz K, López-Maury L, Thompson J, et al. Histone H3 lysine 14 acetylation is required for activation of a DNA damage checkpoint in fission yeast. J Biol Chem. 2012;287:4386–93.PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153:1194–217.PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Hong E, Lim Y, Lee E, Oh M, Kwon D. Tissue-specific and age-dependent expression of protein arginine methyltransferases (PRMTs) in male rat tissues. Biogerontology. 2012;13:329–36.PubMedCrossRefGoogle Scholar
  100. 100.
    Neault M, Mallette FA, Vogel G, Michaud-Levesque J, Richard S. Ablation of PRMT6 reveals a role as a negative transcriptional regulator of the p53 tumor suppressor. Nucleic Acids Res. 2012;40:9513–21.PubMedCentralPubMedCrossRefGoogle Scholar
  101. 101.
    Takahashi Y, Daitoku H, Hirota K, Tamiya H, Yokoyama A, Kako K, et al. Asymmetric arginine dimethylation determines life span in C. elegans by regulating forkhead transcription factor DAF-16. Cell Metab. 2011;13:505–16.PubMedCrossRefGoogle Scholar
  102. 102.
    Love DC, Ghosh S, Mondoux MA, Fukushige T, Wang P, Wilson MA, et al. Dynamic O-GlcNAc cycling at promoters of Caenorhabditis elegans genes regulating longevity, stress, and immunity. Proc Natl Acad Sci U S A. 2010;107:7413–8.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Rahman MM, Stuchlick O, El-Karim EG, Stuart R, Kipreos ET, Wells L. Intracellular protein glycosylation modulates insulin mediated lifespan in C. elegans. Aging (Albany NY). 2010;2:678–90.Google Scholar
  104. 104.
    Jahan S, Davie JR. Protein arginine methyltransferases (PRMTs): role in chromatin organization. Adv Biol Regul. 2015;57:173–84.PubMedCrossRefGoogle Scholar
  105. 105.
    Boulanger M-C, Miranda TB, Clarke S, Di Fruscio M, Suter B, Lasko P, et al. Characterization of the Drosophila protein arginine methyltransferases DART1 and DART4. Biochem J. 2004;379:283–9.PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Hanover JA, Krause MW, Love DC. Bittersweet memories: linking metabolism to epigenetics through O-GlcNAcylation. Nat Rev Mol Cell Biol. 2012;13:312–21.PubMedCrossRefGoogle Scholar
  107. 107.
    Fujiki R, Hashiba W, Sekine H, Yokoyama A, Chikanishi T, Ito S, et al. GlcNAcylation of histone H2B facilitates its monoubiquitination. Nature. 2011;480:557–60.PubMedGoogle Scholar
  108. 108.
    Sakabe K, Hart GW. O-GlcNAc transferase regulates mitotic chromatin dynamics. J Biol Chem. 2010;285:34460–8.PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Myers SA, Panning B, Burlingame AL. Polycomb repressive complex 2 is necessary for the normal site-specific O-GlcNAc distribution in mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2011;108:9490–5.PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Fong JJ, Nguyen BL, Bridger R, Medrano EE, Wells L, Pan S, et al. β-N-Acetylglucosamine (O-GlcNAc) is a novel regulator of mitosis-specific phosphorylations on histone H3. J Biol Chem. 2012;287:12195–203.PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Rønningen T, Shah A, Oldenburg AR, Vekterud K, Delbarre E, Moskaug JØ, et al. Prepatterning of differentiation-driven nuclear lamin A/C-associated chromatin domains by GlcNAcylated histone H2B. Genome Res. 2015.Google Scholar
  112. 112.
    Gagnon J, Daou S, Zamorano N, Iannantuono NVG, Hammond-Martel I, Mashtalir N, et al. Undetectable histone O-GlcNAcylation in mammalian cells. Epigenetics. 2015;10:677–91.PubMedCrossRefGoogle Scholar
  113. 113.•
    Avrahami D, Li C, Zhang J, Schug J, Avrahami R, Rao S, et al. Aging-Dependent Demethylation of Regulatory Elements Correlates with Chromatin State and Improved β Cell Function. Cell Metab. 2015;22:619–32. One of first studies integrating the information on DNA-methylation and histone modifications in ageing, focusing on a selected population of beta-cells, giving insights into cell type-specific epigenetics of ageing. PubMedCrossRefGoogle Scholar
  114. 114.
    Blakeley P, Fogarty NME, Del Valle I, Wamaitha SE, Hu TX, Elder K, et al. Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development. 2015;142:3613.PubMedCentralPubMedCrossRefGoogle Scholar
  115. 115.
    Brind'Amour J, Liu S, Hudson M, Chen C, Karimi MM, Lorincz MC. An ultra-low-input native ChIP-seq protocol for genome-wide profiling of rare cell populations. Nature Commun. 2015;6:6033.CrossRefGoogle Scholar
  116. 116.
    Farlik M, Sheffield NC, Nuzzo A, Datlinger P, Schönegger A, Klughammer J, et al. Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics. Cell Rep. 2015;10:1386–97.PubMedCentralPubMedCrossRefGoogle Scholar
  117. 117.
    Guo M, Wang H, Potter SS, Whitsett JA, Xu Y. SINCERA: a pipeline for single-cell RNA-seq profiling analysis. PLoS Comput Biol. 2015;11:e1004575.PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Kim JK, Kolodziejczyk AA, Illicic T, Teichmann SA, Marioni JC. Characterizing noise structure in single-cell RNA-seq distinguishes genuine from technical stochastic allelic expression. Nature Commun. 2015;6:8687.CrossRefGoogle Scholar
  119. 119.
    Rotem A, Ram O, Shoresh N, Sperling RA, Goren A, Weitz DA, et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol. 2015;33:1165–72.PubMedCrossRefGoogle Scholar
  120. 120.
    Zheng X, Yue S, Chen H, Weber B, Jia J, Zheng Y. Low-cell-number Epigenome profiling aids the study of lens aging and Hematopoiesis. Cell Rep. 2015;13:1505–18.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

Authors and Affiliations

  • Monika Maleszewska
    • 1
  • Julia S. P. Mawer
    • 1
  • Peter Tessarz
    • 1
    • 2
    Email author
  1. 1.Max Planck Research Group Chromatin and AgeingMax Planck Institute for Biology of AgeingCologneGermany
  2. 2.Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD)University of CologneCologneGermany

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