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Apoptosis-Related Histone Modifications Cell Death and Differentiation (2010) 17, 1238–1243 & 2010 Macmillan Publishers Limited All rights reserved 1350-9047/10 $32.00 www.nature.com/cdd Review Cracking the death code: apoptosis-related histone modifications JFu¨llgrabe1, N Hajji1,2 and B Joseph*,1 The degradation and compaction of chromatin are long-standing hallmark features of apoptosis. The histones, chief protein components of chromatin, are subjected to a wide range of post-translational modifications. An increasing body of evidence suggests that combinations of epigenetic histone modifications influence the overall chromatin structure and have clear functional consequences in cellular processes including apoptosis. This review describes the work to date on the post- translational modification of histones during apoptosis, their regulation by enzymatic complexes and discusses the existence of the apoptotic histone code. Cell Death and Differentiation (2010) 17, 1238–1243; doi:10.1038/cdd.2010.58; published online 14 May 2010 Histones are the chief protein components of chromatin, core region.5 Histone modifications function in both long-term acting as spools around which DNA winds, and having a role (i.e. determinants of chromatin conformation) and in more in gene regulation.1 In eukaryotes, an octamer of histones – short-term, ongoing processes (reviewed in Turner6). For the two copies of each of the four core histone proteins H2A, latter, histone modifications can be considered the endpoints, H2B, H3 and H4 – is wrapped by 147 bp of DNA to form a on chromatin, of cellular signaling pathways and a mechanism nucleosome – the fundamental unit of chromatin2 (Figure 1a). through which the genome can respond to environmental In addition, histone H1, located at a position adjacent to the stimuli. An increasing body of evidence suggests that these nucleosome core is involved with the packing of the ‘beads on post-translational histone modifications influence the overall a string’ sub-structures into a higher order structure. In most chromatin structure and have clear functional consequences. eukaryotes, histones are expressed as a family of sequence As a result, work on histone modifications and regulation variants encoded by multiple genes. As different histone of gene expression have coalesced into the ‘histone code’ variants can contribute to a distinct or unique nucleosomal hypothesis, initially proposed by Allis and Turner, that architecture, this heterogeneity can be exploited to regulate a encapsulates the function of histone modifications in chro- wide range of nuclear functions, and evidence is accumulating matin structure and in the regulation of nuclear functions.7,8 that histone variants do indeed have distinct functions. According to the histone code hypothesis, distinct combina- Histones are subjected to a wide variety of post-translational tions of histone modifications are related to specific chromatin- modifications including lysine acetylation, lysine and arginine related functions and processes.9 As recent evidences methylation, serine and threonine phosphorylation and lysine indicate, histone modifications have a role in gene transcription, ubiquitination and sumoylation as well as ADP ribosylation, DNA repair, mitosis, meiosis, development and in apoptosis. all of which are carried out by histone-modifying enzyme Apoptosis, or ‘programmed cell death,’ is an active complexes in a dynamic manner (reviewed in Kouzarides and process fundamental to the development and homeostasis Khorasanizadeh3,4) (Figure 1b). These modifications occur of multicellular organisms. The activation of a genetically primarily within the histone amino-terminal tails protruding controlled cell death program leading to apoptosis results from the surface of the nucleosome as well as on the globular in characteristic biochemical and morphological features that 1Department of Oncology Pathology, Cancer Centrum Karolinska, Karolinska Institutet, Stockholm, Sweden *Corresponding author: B Joseph, Department of Oncology Pathology, Cancer Centrum Karolinska, Karolinska Institutet, R8:03, Stockholm 171 76, Sweden. Tel þ 46 8 517 738 26; Fax þ 46 8 33 9031; E-mail: [email protected] 2Current address: Division of Investigative Science, Department of Experimental Medicine and Toxicology, Imperial College London, London, UK. Keywords: apoptosis; histone modification; epigenetic Abbreviations: ac, acetylated; ATM, ataxia telangiectasia mutated; BRCA1, breast cancer 1, early onset; Chk2, CHK2 checkpoint homolog (Schizosacchar- omyces pombe); DFF40, DNA fragmentation factor 40; DNA-PK, DNA-dependent protein kinase; EYA, mammalian homologue of the Drosophila eyes absent; H2A, histone 2A; H2B, histone 2B; H3, histone 3; H4, histone 4; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDACI, HDAC inhibitor; HDM, histone demethylase; hMOF, human orthologue of the Drosophila melanogaster males absent on the first gene; HMT, histone methyltransferase; K, lysine; MDC1, mediator of DNA damage checkpoint protein 1; me, methylated; MRE11, meiotic recombination 11 homolog A (Saccharomyces cerevisiae); Mst1, mammalian sterile twenty kinase 1; NBS1, Nijmegen breakage syndrome 1 (nibrin); NF-kB, nuclear factor k-light-chain-enhancer of activated B cells; ph, phosphorylated; PKCd, protein kinase C-d; R, arginine; RAD50, RAD50 homolog (S. cerevisiae); Ran, ras-related nuclear protein; RanBP1, Ran-specific GTPase-activating protein; RanGAP1, Ran GTPase-activating protein 1; RCC1, regulator of chromosome condensation 1; S, serine; SIRT1, sirtuin 1; T, threonine; ub, ubiquitinylated; WICH complex, WSTF–ISWI ATP-dependent chromatin-remodeling complex; WSTF, Williams–Beuren syndrome transcription factor; 53BP1, p53-binding protein 1 Received 17.2.10; revised 07.4.10; accepted 14.4.10; Edited by G Melino; published online 14.5.10 Apoptotic histone code JFu¨llgrabe et al 1239 Figure 1 Chromatin structure and histone-modifying enzymes. (a) Chromatin is made of repeating units of nucleosomes, which consist of B147 base pairs of DNA wrapped around a histone octamer consisting of two copies of each of the core histones H2A, H2B, H3, and H4. Linker histone H1 is positioned on top of the nucleosome core particles stabilizing higher order chromatin structure. The histones are subject to a wide variety of post-translational modifications, primarily on their N-terminal tails, but also in their globular core region. (b) The dynamic nature of histone modifications. The modifications that occur on histone tails are shown together with the enzymes that lay down and remove the marks. ac, acetylated; HAT, histone acetyltransferase; HDAC, histone deacetylase; HDM, histone demethylase; HMT, histone methyltransferase; me, methylated; ph, phosphorylated; ub, ubiquitinylated take place both outside and inside the nucleus. Chromatin mark – and how these marks may affect chromatin function condensation paralleled by DNA fragmentation is one of the and structure during cell death (Figure 2). most important nuclear events occurring during apoptosis.10 Owing to the regulated nature of apoptosis, epigenetic Apoptotic Dephosphorylated Histone H1: the Lost Mark? features are likely to have a major role in the nuclear changes One of the first histone post-translational modifications experienced by apoptotic cells. suggested to be linked to the apoptotic process was the Histone modifications, and in particular phosphorylation dephosphorylation of histone H1. Linker histone H1 is highly and acetylation, have long been suggested to affect chromatin phosphorylated in normal growing cells. A correlation be- function and structure during cell death. A decade ago, Lee tween early apoptotic dephosphorylation of histone H1 and et al.11 established, using inhibitors of protein phosphatase, the onset of typical chromatin oligonucleosomal fragmenta- that phosphorylation of histones may be involved in thymocyte tion has been described.15,16 Two lines of evidence point to apoptosis. This observation was later confirmed during histone H1 contribution to internucleosomal chromatin clea- astrocyte apoptosis.12 Histone acetylation has long been vage. First, H1 histones are associated with the linker DNA, known to maintain the chromatin in an open and accessible which connects two adjacent nucleosomes and is the site of conformation to accommodate the transcriptional machinery DNA cleavage during apoptosis. Second, linker histones and to have a major role in regulating gene expression. In a enhance the activity of DNA fragmentation factor 40 (DFF40/ study of the structural changes that occur in chromatin of CAD), the nuclease that cleaves DNA during apoptosis. apoptotic cells, Allera et al.13 reported that histones became However, recent investigation revealed that there is no strict deacetylated in rat thymocytes that were induced to undergo correlation between initial apoptotic histone H1 dephosphor- apoptosis by glucocorticoids. Collectively, these results ylation and the onset of apoptotic DNA fragmentation. Histone support the idea that chemical modification of histones is H1 dephosphorylation is neither a prerequisite for nor an involved in the chromatin alterations in cells undergoing absolute consequence of internucleosomal cleavage. More- apoptosis. In fact, it has further been shown that phospho- over, the phosphorylation state of H1 histones does not seem rylation of histone H2A, H2B, H3 and H4, dephosphorylation to influence the activation effect of H1 histones on the activity of histone H1, acetylation of histone H2B, H4, hypoacetylation of DFF40.17
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