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Review
. 2012 Nov;37(11):466-76.
doi: 10.1016/j.tibs.2012.08.001. Epub 2012 Sep 6.

The great unravelling: chromatin as a modulator of the aging process

Roderick J O'Sullivan  1 , Jan Karlseder
Affiliations
Review

The great unravelling: chromatin as a modulator of the aging process

Roderick J O'Sullivan et al. Trends Biochem Sci. 2012 Nov.

Abstract

During embryogenesis, the establishment of chromatin states permits the implementation of genetic programs that allow the faithful development of the organism. However, these states are not fixed and there is much evidence that stochastic or chronic deterioration of chromatin organization, as correlated by transcriptional alterations and the accumulation of DNA damage in cells, occurs during the lifespan of the individual. Whether causal or simply a byproduct of macromolecular decay, these changes in chromatin states have emerged as potentially central conduits of mammalian aging. This review explores the current state of our understanding of the links between chromatin organization and aging.

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Figures

Figure 1
Figure 1. Aging is due to an increased disequilibrium in cellular homeostasis
The decline in metabolic rates and telomere shortening over time can contribute to structural and gene expression changes that are associated with aging. By contrast, chronic exposure to reactive oxygen species (ROS), DNA damage and replicative stress can cooperatively cause elevated stochastic transcriptional noise. Structural changes in chromatin and the regulation of chromatin modifiers might be common denominators that underlie how these factors affect chromosomal stability and the cellular processes that drive the aging process.
Figure 2
Figure 2. Chromatin modifiers linked with age-related transcriptional deregulation
(a) Left: In young cells the repression of the p16INK4A gene is under the purview of the PRC1 and PRC2 polycomb repressive complexes. PRC2 consists of polycomb group proteins such as Pc and Enhancer of zeste-2, EZH2. EZH2 methylates chromatin at H3K27me3 (purple triangle) throughout the locus. PRC2, in turn, recruits the PRC1 complex, consisting of BMI1 and RING1 which ubiquitylate H2AK119 (yellow circle) and ‘lock in’ the inactivate state of the locus. The long non-coding RNA, ANRIL (shown as dark blue line) and looping between distal PREs might contribute in p16INK4A suppression. Right: In old cells this repressive domain switches from polycomb-mediated repression to trithorax (shown as mixed lineage leukemia 1, MLL1)-dependent transcriptional activation. First, H3K27me3 is removed by the H3K27me3 specific lysine demethylase, KDM Jumonji D3, JMJD3, and then MLL1 mediates H3K4me3 (green triangle) at the p16INK4A promoter to facilitate gene expression (RNA shown as blue lines). (b) Left: in young cells SIRT1 localizes to repetitive elements (broken DNA line) and genes to deacetylate H1K26 (blue hexagon); this maintains transcriptional repression and promotes heterochromatic chromatin modifications such as H3K9me3 (red triangle). Right: following DNA damage, SIRT1 is mobilized to DNA damage sites to participate in DNA repair. This leads to activation of SIRT1-regulated genes and transcription of repetitive elements. As the expression of SIRT1 decreases, elevated transcriptional deregulation and the accumulation of unrepaired DNA damage lesions can promote aging. (c) Left: in young cells SIRT6 binds to NFKB and blocks transcriptional activation by de-acetylating H3K9ac (blue hexagon) at NFKB target promoters. Transcriptional silencing of NFKB target promoters might be maintained by H3K27me3 (purple triangle)-dependent repression. Right: in old cells, SIRT6 might be titrated away from NFKB. As a result, the full transcriptional activation of NFKB and its target genes is unleashed. This is likely to involve the trithorax complex and MLL1-mediated H3K4me3 (green triangle).
Figure 3
Figure 3. Senescence associated heterochromatic foci (SAHF)
Senescence associated heterochromatic foci are sub-nuclear structures that consist of DNA, chromatin and proteins such as histone macroH2A, high-mobility group protein A, HMGA, Anti-silencing factor 1, ASF1, HIR histone cell cycle regulation defective homolog A, HIRA, heterochromatin protein 1-γ isoform, HP1γ and H3K9me3 (red triangle), that are encapsulated in large Pro-Myelocytic leukemia, PML, bodies (shown as large blue circle with dashed border line). SAHF are formed in response to oncogene-induced hyper-replication, which and leads to activation of the ATR checkpoint and the up-regulation of p16INK4A/p53 tumour suppressors. SAHF are postulated to subdue the potency of the DNA damage response and prevent tumorigenesis.
Figure 4
Figure 4. Histone loss during aging in S. cerevisiae and human cells
(a) Yeast cells. Left panels: regulation of histone genes. Top: In young yeast cells the functional cooperation between Regulator of Ty1 transposition protein 109, RTT109 and Anti-silencing factor 1, ASF1 (green and yellow ovals, respectively) promotes H3K56ac (blue hexagons) at histone gene promoters to drive histone gene expression. Bottom: in old yeast cells there are less histone proteins available. This leads to nucleosome loss at histone genes, permitting increased accessibility for RNA Polymerase II (RNAP) and leading to increased histone transcription and greater histone mRNA yields. Though the precise mechanism of histone loss is unclear, it might be due to changes in the expression of RTT109 and ASF1 and reduced levels of H3K56ac. Right panels: certain heterochromatic genomic loci. Top: in young cells, the integrity of genomic loci such as the MAT locus, rDNA loci and telomeres is maintained by the histone deacetylase SIR2 (blue oval), which removes H4K16ac and potentially other acetylation chromatin marks (blue hexagons). Bottom: in the absence of histones, ASF1, and H3K56ac, the KAT SAS2 acetylates H4K16ac at target loci. This might promote transcription of these loci and inhibit nucleosome assembly. (b) Mammalian cells. Left panels: histone genes. Top: In young human cells, histone mRNA is stabilized by the association of SLBP (yellow oval) and translated to new histone proteins. Bottom: in old cells, DNA damage might constrain expression and activity of SLBP (red arrow) leading to the disruption of histone mRNA maturation and translation. Right panels: genomic loci (telomeres). Top: In young cells, ASF1 might regulate the supply of histones at genomic loci including telomeres. ASF1 promotes the establishment of chromatin modifications, H3K56ac (blue hexagon) and H3K9me1 (red triangle) at chromatin. Bottom: In old cells, in conjunction with diminished levels of histone mRNA, the absence of ASF1 might diminish chromatin assembly dynamics and lead to loss of nucleosomes at telomeres and potentially other regions. Reduced nucleosome occupancy might promote telomere dysfunction (red arrow) and accumulation of γH2AX (purple circle).
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References

    1. Campisi J, Vijg J. Does damage to DNA and other macromolecules play a role in aging? If so, how? J Gerontol A Biol Sci Med Sci. 2009;64:175–178. - PMC - PubMed
    1. Margueron R, Reinberg D. Chromatin structure and the inheritance of epigenetic information. Nat Rev Genet. 2010;11:285–296. - PMC - PubMed
    1. Sedivy JM, et al. Aging by epigenetics--a consequence of chromatin damage? Exp. Cell Res. 2008;314:1909–1917. - PMC - PubMed
    1. Herskind AM, et al. The heritability of human longevity: a population-based study of 2872 Danish twin pairs born 1870–1900. Hum. Genet. 1996;97:319–323. - PubMed
    1. Fraga MF, et al. Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci USA. 2005;102:10604–10609. - PMC - PubMed

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