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The Role of Nuclear Architecture in Genomic Instability and Ageing

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The Role of Nuclear Architecture in Genomic Instability and Ageing REVIEWS The role of nuclear architecture in genomic instability and ageing Philipp Oberdoerffer and David A. Sinclair Abstract | Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time — a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA–protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms. Senescence Chromosomes are arguably the most difficult structures Although chromatin reorganization was linked to A nearly irreversible stage a cell has to maintain over a lifetime. The DNA in each ageing in budding yeast over 10 years ago8,9, these ideas of permanent G1 cell-cycle chromosome experiences thousands of chemical altera- have remained untested. Recently, a growing appre- arrest, which is linked to tions and DNA breaks in a single day, and the informa- ciation for the importance of chromatin in regulating morphological changes, metabolic changes and tion each encodes requires strict regulation to maintain gene expression and maintaining genomic integrity in changes in gene expression. cellular identity and function. To manage these tasks, complex organisms has reinvigorated interest in the link The induction of senescence eukaryotes have evolved a complex packaging system between chromatin alterations and ageing. In the past depends on p53 and cell-cycle known as chromatin, in which DNA is wrapped around 10 years, advances in nuclear imaging technologies have inhibitors such as p21 and p16. a protein core of four different histone dimers and forms a revealed a high level of chromatin organization that is nucleosome, the basic building block of chromatin. known as the nuclear architecture. In fact, genes from Recent studies have indicated that chromatin is a highly different chromosomes are often in close physical prox- dynamic form of nuclear organization that influences imity and form discrete foci dubbed transcription fac- DNA stability and gene-expression patterns1,2. The level tories, which help to orchestrate their transcription and of chromatin compaction can be modulated through organize the genome in the three-dimensional nuclear the chemical modification of histones (BOX 1) or of space (reviewed in REF. 10). DNA. The more densely the nucleosomes are packed, The long-term maintenance of the nuclear archi- the more protected is the DNA from chromosomal tecture is vital for the normal functioning of cells damage3, but the less accessible it is for transcription2. and tissues over a lifetime. The dramatic effect of Highly compacted, transcriptionally silent chromatin a disturbed nuclear architecture is exemplified by is known as heterochromatin, whereas more accessible Hutchinson–Gilford progeria syndrome (HGPS), in chromatin is known as euchromatin (BOX 2). which a mutation that disrupts the nuclear architecture Unfortunately, the eukaryotic system of DNA leads to a disease with symptoms that resemble aspects Department of Pathology, packaging is not immune to the ravages of time. All of normal human ageing, such as loss of hair, restricted Paul F. Glenn Laboratories eukaryotes, including humans, experience changes in joint mobility and atherosclerosis11. Even cells from nor- for the Biological chromatin organization and gene-expression patterns mal individuals undergo significant nuclear architecture Mechanisms of Aging, 12 Harvard Medical School, as they age. In the late 1990s, a few researchers proposed changes in response to stress , and there are early hints 77 Avenue Louis Pasteur, that changes in chromatin organization underlie ageing- that normal human ageing is associated with alterations Boston, Massachusetts, USA. related changes in gene expression and the ageing in nuclear architecture13. Correspondence to D.S. process4,5. Changes in gene expression were already In this review, we discuss the causes and conse- e-mail: david_sinclair@hms. known to contribute to cellular senescence6, a possible quences of changes in nuclear architecture with age. harvard.edu 7 doi:10.1038/nrm2238 cause of ageing , and may provide an explanation for We focus on the role of epigenetic gene regulation dur- Published online the age-related decline in organ and tissue function in ing the ageing process, with an emphasis on drawing 15 August 2007 complex organisms. parallels between observations in yeast and mammals. 692 | septeMBer 2007 | VOLUME 8 www.nature.com/reviews/molcellbio © 2007 Nature Publishing Group FOCUS ONREVIEWS AGeiNG Box 1 | Epigenetic silencing and the histone code Epigenetic silencing describes heritable changes in gene Class I HDACs expression that do not involve modifications in coding Class III HDACs sequences. These changes include the methylation of Class II HDACs (sirtuins) HATs cytidine residues in genomic DNA or the modification of histones. Histones constitute the building blocks of a Remove Add protein core, around which DNA is wrapped to form a nucleosome, the fundamental packing unit of chromatin. These protein cores consist of two subunits of histones Me Me Ac Ac H2A, H2B, H3 and H4. Histone H1 is a linker histone that Me Me Ac Ac Ac helps to pack neighbouring nucleosomes together tightly75. Although most of each histone complex is inaccessible, histone tails protrude from the nucleosomes and are subject to post-translational modifications. These Add Remove modifications affect the secondary structure of histones and, thereby, the compaction of nucleosomes. Densely packed nucleosomes are generally inaccessible to the HMTs LSD1 transcription machinery and form epigenetically silent Jumonji family heterochromatin, whereas less compact nucleosomes are known as transcriptionally active euchromatin. Histone modifications include phosphorylation, methylation, acetylation, ubiquitylationNatur ande Re ADP-ribosylation.views | Molecular CeAllll of Biolog y these modifications are reversible, allowing for dynamic epigenetic gene regulation. Histone phosphorylation has mainly been associated with cell-cycle-mediated changes to chromatin and has a role in the DNA-damage response. Phosphorylated histone H2AX (or H2A in yeast) recruits the DNA-repair machinery and helps to resolve DNA double-strand breaks. The roles of ubiquitylation and ADP ribosylation are still not fully understood. Methylation and acetylation marks on histones are central to the regulation of the secondary structure of chromatin and for epigenetic silencing. Histone methylation is often associated with a repressed chromatin state, whereas acetylation generally coincides with transcriptionally active chromatin. Histone demethylases (such as the Jumonji family of enzymes) and histone acetyltransferases (HATs) are often involved in gene activation, whereas histone methyltransferases (HMTs) and histone deacetylases (HDACs) are important for the establishment and maintenance of heterochromatin, although there are exceptions (see figure). Changes in the expression levels or in the subnuclear localization of these enzymes (caused by DNA damage or over the lifetime of the organism) can be expected to affect nuclear architecture and gene-expression patterns (reviewed in REF. 76). Ac, acetylation; LSD1, lysine-specific histone demethylase-1; Me, methylation. We propose that a conserved DNA-damage response Sir2 mediates heterochromatin formation. One of the induces cumulative changes in chromatin structure and key regulators of yeast heterochromatin is Sir2 (silent nuclear architecture that are important driving forces information regulator-2), an NAD+-dependent histone behind the inexorable changes that occur in organisms deacetylase that predominately removes acetyl groups over time. These changes include a decline in genomic from Lys16 of histone H4 (REF. 15). At the mating-type integrity, alterations in gene transcription and a loss of genes and telomeres, Sir2 interacts with its structural Mating-type locus (REFS 16,86) The mating of yeast only vitality — the series of changes we commonly refer to partners Sir3 and Sir4 , which regulate occurs between haploids, as ageing. and direct its deacetylase activity. Binding of the which can be either mating Sir4–Sir2 heterodimer to DNA nucleates DNA silencing type a or mating type α. The Heterochromatin alterations in yeast by recruiting Sir3 to form the Sir complex. Driven by mating type is determined by a single locus (MAT). Gene In the 1990s, a series of discoveries in the budding Sir2-dependent histone deacetylation, the Sir complex conversion between MAT and yeast Saccharomyces cerevisiae identified a mechanis- promotes heterochromatin formation by spreading the silent mating-type loci HML tic link between epigenetic silencing and ageing. The along chromatin through cycles of recruitment of other and HMR allows haploid yeast replicative age of a yeast cell is the number of offspring Sir complexes86. to switch to the active mating it produces before undergoing senescence (~23–30). At the rDNA locus, Sir2 is a crucial component of a type as often as every cell cycle. Like in all eukaryotes, heterochromatin in yeast serves network of protein–protein interactions that regulate two main purposes: it maintains
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