Nuclear events such as chromatin condensation, DNA cleavage at internucleosomal sites, and histone release from chromatin are recognized as hallmarks of apoptosis. However, there is no complete understanding of the molecular events underlying these changes. It is likely that epigenetic changes such as DNA methylation and histone modifications that are involved in chromatin dynamics and structure are also involved in the nuclear events described. In this report we have shown that apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. Most importantly, we have observed a particular epigenetic signature for early apoptosis defined by a release of hypoacetylated and trimethylated histone H4 and internucleosomal fragmented DNA that is hypermethylated and originates from perinuclear heterochromatin. These findings provide one of the first links between apoptotic nuclear events and epigenetic markers. Nuclear events such as chromatin condensation, DNA cleavage at internucleosomal sites, and histone release from chromatin are recognized as hallmarks of apoptosis. However, there is no complete understanding of the molecular events underlying these changes. It is likely that epigenetic changes such as DNA methylation and histone modifications that are involved in chromatin dynamics and structure are also involved in the nuclear events described. In this report we have shown that apoptosis is associated with global DNA hypomethylation and histone deacetylation events in leukemia cells. Most importantly, we have observed a particular epigenetic signature for early apoptosis defined by a release of hypoacetylated and trimethylated histone H4 and internucleosomal fragmented DNA that is hypermethylated and originates from perinuclear heterochromatin. These findings provide one of the first links between apoptotic nuclear events and epigenetic markers. Apoptosis is a form of cell death essential for the morphogenesis, development, differentiation, and homeostasis of eukaryotic multicellular organisms. The activation of a genetically controlled cell death program leading to apoptosis results in characteristic biochemical and morphological features that take place both outside and inside the nucleus (1Lawen A. BioEssays. 2003; 25: 888-896Crossref PubMed Scopus (350) Google Scholar). The biochemical mechanisms responsible for key nuclear events, such as chromatin condensation, DNA fragmentation, and release of nuclear proteins, although commonly used as markers for apoptosis, are not fully understood (2Martelli A.M. Zweyer M. Ochs R.L. Tazzari P.L. Tabellini G. Narducci P. Bortul R. J. Cell. Biochem. 2001; 82: 634-646Crossref PubMed Scopus (132) Google Scholar). The regulated nature of apoptosis makes it likely that nuclear changes experienced by apoptotic cells are mediated by epigenetic markers. This epigenetic information is basically stored as DNA methylation and post-translational histone modifications. These two groups of modifications play an active role in organizing, compartmentalizing, and regulating genetic information encoded in DNA by defining nuclear architecture, and gene expression (3Khorasanizadeh S. Cell. 2004; 116: 259-272Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar). With regard to gene regulation, the major functional consequence of DNA methylation is the repression of transcription (4Cedar H. Cell. 1988; 53: 3-4Abstract Full Text PDF PubMed Scopus (727) Google Scholar). In the case of histone modifications, the type of modification (acetylation, methylation, phosphorylation, etc.) and the specific amino acid residue that is modified determine the functional effect. Histone modifications also determine the nature of chromatin regions, such as heterochromatin. For example, the inactive X chromosome is characterized by trimethylation of Lys-27 of H3 and dimethylation of Lys-9 of H3 (5Plath K. Fang J. Mlynarczyk-Evans S.K. Cao R. Worringer K.A. Wang H. de la Cruz C.C. Otte A.P. Panning B. Zhang Y. Science. 2003; 300: 131-135Crossref PubMed Scopus (945) Google Scholar, 6Silva J. Mak W. Zvetkova I. Appanah R. Nesterova T.B. Webster Z. Peters A.H. Jenuwein T. Otte A.P. Brockdorff N. Dev. Cell. 2003; 4: 481-495Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar, 7Okamoto I. Otte A.P. Allis C.D. Reinberg D. Heard E. Science. 2004; 303: 644-649Crossref PubMed Scopus (615) Google Scholar), whereas Lys-9 trimethylation and Lys-27 monomethylation of H3 and Lys-20 trimethylation of H4 are characteristic of pericentric heterochromatin (8Peters A.H. Kubicek S. Mechtler K. O'Sullivan R.J. Derijck A.A. Perez-Burgos L. Kohlmaier A. Opravil S. Tachibana M. Shinkai Y. Martens J.H. Jenuwein T. Mol. 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Wesierska-Gadek J. Int. J. Cancer. 2003; 106: 486-495Crossref PubMed Scopus (80) Google Scholar), although some authors have interpreted this result to be a loss of hyperacetylated histones by degradation rather than the consequence of the active hypoacetylation of histones during apoptosis (19Hendzel M.J. Nishioka W.K. Raymond Y. Allis C.D. Bazett-Jones D.P. Th'ng J.P. J. Biol. Chem. 1998; 273: 24470-24478Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). Thus, there is a need to clarify the role of these modifications in different nuclear events during apoptosis. Regarding apoptotic release of histones and other nuclear proteins, it has been proposed that this process is associated with chromatin condensation and DNA fragmentation (20Wu D. Ingram A. Lahti J.H. Mazza B. Grenet J. Kapoor A. Liu L. Kidd V.J. Tang D. J. Biol. Chem. 2002; 277: 12001-12008Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 21Scaffidi P. Misteli T. Bianchi M.E. 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In this we have the global of histone modification and DNA methylation changes associated with the apoptotic in particular in with the release of nuclear to the global deacetylation of histones H3 and H4 associated with release during apoptosis has been Most we have a of post-translational modifications that is characteristic of histones early in apoptosis. histone H4 is hypoacetylated and trimethylated at whereas histone H3 is and These histones are and with fragmented DNA with a than the DNA that in the This DNA originates in the perinuclear of the These with the observed of modification of suggest that the results from the degradation of perinuclear heterochromatin and internal structures of the nucleus early in apoptosis. and cells in modified with The H3 a of H3, histone H3 Lys-9 histone H3 histone H3 histone H3 Lys-9 histone H3 histone H4 histone H4 histone H4 histone H4 and histone H4 and used as apoptosis Apoptosis the apoptosis This is the of the that apoptotic cells that remain to cell cells are not with are by of and cells to or of and for C.A. K. C.A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Apoptosis by of from cell by acid by Scholar). the release of histone to the during apoptosis, we with and as in (20Wu D. Ingram A. Lahti J.H. Mazza B. Grenet J. Kapoor A. Liu L. Kidd V.J. Tang D. J. Biol. Chem. 2002; 277: 12001-12008Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). are in this a cell the and a nuclear In this the to the acid for at for and with by acid as of Histone by of histone acetylation by a modification of a H. W. A. M. B. Biochem. J. PubMed Scopus (64) Google Scholar, G. L. M. M. A. E. M. S. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). histones by used a with an in acid E. C. L. J. Biol. Chem. 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The DNA from of the with by and the DNA with The a with a and the for with DNA and cells in for at or for and with for at as J. E. A. A. M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). DNA from the cell with used to cells. a with and and in Histone during a first to a between epigenetic and nuclear changes in apoptosis, we global changes in the modification of histones during apoptosis by A change in the of histone modifications could be associated with morphological changes that in the nucleus in apoptosis. cells with and acid histones at different For the of apoptosis by the global hyperacetylated of histones H3 and H4 and the form at specific of histone H3 and histone H4 and other modifications, such as and of histone H3, also first observed a decrease in global of histone H4 acetylation in apoptotic However, at specific of H4 and a loss of acetylation during apoptosis. of acetylation observed at and These results are with that also suggest that the acetylation of the and one and and the are R.G. Allis C.D. Nature. 1996; Scopus Google Scholar). In to no changes in acetylation global or observed for histone phosphorylation of and methylation of and Lys-9 of H3 to remain the changes observed associated with acetylation an used to changes in histone acetylation of H3 and The the of histones by by T. A. 2003; Scopus Google Scholar, M. 2002; PubMed Scopus Google Scholar, M.J. J. 1998; PubMed Google Scholar). This the and of of histones H3 and In this for histone H4 of the and histone as a of The first and of the been as and histone E. A. M. J. G. T. C. K. S. A. E. A. N. A. C. Jenuwein T. M. PubMed Scopus Google Scholar). of Lys-20 in H4 is a of heterochromatin G. Lachner M. Sarma K. Ebert A. Sengupta R. Reuter G. Reinberg D. Jenuwein T. Genes. Dev. 2004; 18: 1251-1262Crossref PubMed Scopus (843) Google Scholar, K. Sarma K. H. J. Wang Y. S. P. P. R. Allis C.D. Reinberg D. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, N. P. S. P. R. S. G. L. S. W. R. J. Cell Sci. 2004; PubMed Scopus Google Scholar) and B. E. W. I. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). In of and in the of H4 observed with in for the apoptosis and apoptosis The results for cells also of and of H4 for the apoptosis and In the case of histone H3, of cells with and in of and of These with an in the form of results with cells not These not been observed to changes in the acetylation of H3, although the that this is a the other it is that the not and that are by the decrease in acetylation of H3 than the observed for Histone H4 from in Apoptosis and the global changes in histone H3 and H4 modifications, we the specific modifications by histones that are from the nucleus during apoptosis L. Perez D. White E. J. Cell Biol. 1996; 135: 1441-1455Crossref PubMed Scopus (511) Google Scholar) with that are Thus, we apoptosis with and and the cells with a these in cells are the of nucleus is (20Wu D. Ingram A. Lahti J.H. Mazza B. Grenet J. Kapoor A. Liu L. Kidd V.J. Tang D. J. Biol. Chem. 2002; 277: 12001-12008Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, J. Biol. Chem. Full Text PDF Google Scholar), it is to histones to the in apoptosis from in the two that we cell to the and nuclear from the cell of In apoptotic we observed a of histones in the cell in from the nucleus during apoptosis. The of histones a of that in the apoptosis The of H4 by that histones in the nuclear not between and apoptotic the results histone H4 been there in histone H4 However, a of cell with nuclear in the modification of histone Histone H4 from cell to be hypoacetylated with in apoptotic nuclear with an to decrease in the form of histone H4 during early apoptosis in H4 acetylation between and histone H4 at Thus, apoptosis histone H4 in hypoacetylated and the of as apoptosis and the histones in the nuclear However, the histone H4 modification that and H4 different of Most the characteristic to different methylation of histone H4 from both and whereas the cell the trimethylated form of histone the nuclear the form for apoptosis This is from the of the of these two of the that to the and trimethylated of H4 been during the of the histones These that apoptosis of histone H4 trimethylated in the cell and This specific release of trimethylated H4 as apoptosis and of the trimethylation of histone H4 to and to the release of H4 trimethylation and hypoacetylation of histone H4 are specific features of the histone from during early apoptosis. This specific of trimethylated and hypoacetylated histones in the is at of apoptosis, histones the histones in the of of Histone H3 and H4 during Apoptosis by and the acetylation of we global hyperacetylated histones H3 and H4 and apoptotic cell with nuclear also used specific different in to changes in acetylation at particular a decrease of global both for histone H3 and observed in cell with histones from the nuclear However, whereas the in acetylation of histone H3 between cell nuclear during the of apoptosis, histone H4 characterized by a change in this Thus, whereas H4 in the nuclear a decrease in in with the shown histone H4 in the cell at apoptosis The of the of H4 and that histone H4 in than the H4 in the nuclear In a acetylation of and a to global acetylation and in the cell as apoptosis whereas no changes observed in the acetylation of and of these that histone H4 of the apoptotic cell hypoacetylated to and nuclear shown by and that to in of histone H4 in the It be observed that of histone in whereas of histone in and there no in acetylation of in cell the other histone H3 a of modification for modifications it and than histones from the nuclear the of H3 of and Lys-9 a DNA in Apoptosis with to DNA in the methylation and acetylation have been shown to be to DNA methylation Cell Mol. Sci. 2001; PubMed Scopus Google Scholar). the observed in histone methylation and acetylation during apoptosis and cell and nuclear to the of changes in DNA methylation during apoptosis. the other it is that changes in DNA methylation could in the apoptotic in a to in other 1999; PubMed Scopus Google Scholar, M. 2002; PubMed Scopus Google Scholar). DNA by a from of cells with at different The of the of the a The of from in cells to apoptosis These although the of changes experienced during M. 2002; PubMed Scopus Google Scholar, S. M. M. M. 2003; Google Scholar). The observed decrease in the of DNA from could be of the DNA between the nucleus and during apoptosis, to the observed for histone modifications. DNA from the two nuclear for the DNA from the and cell the DNA during apoptosis be DNA and by we observed the characteristic apoptotic internucleosomal fragmentation with chromatin of in the DNA from the apoptotic cell whereas the DNA from the apoptotic nuclear fragmentation DNA from the apoptotic and cell by to The in methylation in the apoptotic cell whereas there no the nuclear DNA to apoptotic cell a of of than that of the cell This is with that in chromatin with a of of are in cells. The hypermethylated of with the hypoacetylation of the histones and trimethylation of H4 in the that the heterochromatin may be the of the DNA and histones during apoptosis. DNA during Apoptosis from with the of the nuclear during apoptosis, DNA from the apoptotic cell with and used as a to the of DNA during apoptosis. In this DNA from the cell DNA from cells in The of an of the not that DNA a used DNA in nuclear in cells. This be used to the nuclear of the fragmented DNA a cell as a The nuclear of the DNA associated with the apoptotic the of at the nuclear that the DNA in the perinuclear of the nucleus chromatin with the nuclear membrane heterochromatin A. J. C. G. J. 1996; PubMed Scopus Google Scholar, D. N. H. K. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, M. Dev. 1999; PubMed Scopus Google Scholar, H. N. A. T. 2001; PubMed Scopus Google Scholar) This result is with the of the DNA that a Histone modifications play key in different DNA and chromatin condensation in (3Khorasanizadeh S. Cell. 2004; 116: 259-272Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar). of the events in apoptosis changes in the chromatin condensation, DNA fragmentation, and release of nuclear proteins (2Martelli A.M. Zweyer M. Ochs R.L. Tazzari P.L. Tabellini G. Narducci P. Bortul R. J. Cell. Biochem. 2001; 82: 634-646Crossref PubMed Scopus (132) Google Scholar, D. Ingram A. 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Chem. 1998; 273: 24470-24478Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar) that global decrease of histone acetylation could be the result of a loss degradation in the of hyperacetylated histones from during early apoptosis and that this a in global However, results that histones during early apoptosis hypoacetylation than in the A of the apoptotic cell the histones are and nuclear that global hypoacetylation in the that histones from hypoacetylated and not hyperacetylated this not the of specific degradation of hyperacetylated of the from both cell and nuclear not degradation of histones H3 and H4 of Histone H4 with during of the findings of this is that the of histone H4 from chromatin in early apoptosis is This trimethylation has been to at Lys-20 E. A. M. J. G. T. C. K. S. A. E. A. N. A. C. Jenuwein T. M. PubMed Scopus Google Scholar). it is likely that H4 Lys-20 trimethylation as a or for chromatin degradation and we the that it may play an active role as a for nuclear or in these Thus, histone H4 trimethylation could as a in a to other post-translational modifications that different nuclear to chromatin A.P. Dev. PubMed Scopus Google Scholar, Allis C.D. Biol. 1999; PubMed Scopus Google Scholar) in the context of the histone Allis C.D. Nature. 2000; PubMed Scopus Google Scholar). at or in with other modifications such as could as a for that are of DNA fragmentation chromatin condensation, in the case of that DNA or the are associated with chromatin and DNA during Apoptosis in the of the epigenetic and to histones and DNA from apoptotic cell that the from the nucleus in apoptosis has a perinuclear at during the DNA from apoptotic cell is hypermethylated and used as a for perinuclear the other histones are hypoacetylated and histone H4 is trimethylated at a characteristic epigenetic of heterochromatin (8Peters A.H. Kubicek S. Mechtler K. O'Sullivan R.J. Derijck A.A. Perez-Burgos L. Kohlmaier A. Opravil S. Tachibana M. Shinkai Y. Martens J.H. Jenuwein T. Mol. Cell. 2003; 12: 1577-1589Abstract Full Text Full Text PDF PubMed Scopus (895) Google Scholar, 9Schotta G. Lachner M. Sarma K. Ebert A. Sengupta R. Reuter G. Reinberg D. Jenuwein T. Genes. Dev. 2004; 18: 1251-1262Crossref PubMed Scopus (843) Google Scholar, K. Sarma K. H. J. Wang Y. S. P. P. R. Allis C.D. Reinberg D. Mol. Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, B. E. W. I. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar, B. J. Shinkai Y. Allis C.D. Mol. Cell. 2003; 12: Full Text Full Text PDF PubMed Scopus Google Scholar). In fact, we have that trimethylated histone H4 at Lys-20 is associated with and other E. A. M. J. G. T. C. K. S. A. E. A. N. A. C. Jenuwein T. M. PubMed Scopus Google Scholar) that are to be of heterochromatin. nuclear structures degraded apoptotic chromatin condensation and DNA fragmentation, (22Lazebnik Y.A. Cole S. Cooke C.A. Nelson W.G. Earnshaw W.C. J. Cell Biol. 1993; 23: 7-22Crossref Scopus (424) Google Scholar, 23Rao L. Perez D. White E. J. Cell Biol. 1996; 135: 1441-1455Crossref PubMed Scopus (511) Google Scholar, 24Weaver V.M. Carson C.E. Walker P.R. Chaly N. Lach B. Raymond Y. Brown D.L. Sikorska M. J. Cell Sci. 1996; 109: 45-56Crossref PubMed Google Scholar, S. B. J. Biol. 2000; PubMed Scopus Google Scholar). These heterochromatin structures by chromatin is to the nuclear membrane A. J. C. G. J. 1996; PubMed Scopus Google Scholar, D. N. H. K. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar, H. N. A. T. 2001; PubMed Scopus Google Scholar, S. N. P. 2004; 12: PubMed Scopus (49) Google Scholar). This is in of the that histone H4 and fragmented DNA and in the cell are a consequence of the perinuclear heterochromatin degradation described. It has been proposed that chromatin condensation during apoptosis of a process of In the first is be or by the degradation of both the nuclear and of the during early apoptosis. The and of heterochromatin to the characteristic apoptotic chromatin condensation. there be a degradation process of the heterochromatin that the characteristic DNA (19Hendzel M.J. Nishioka W.K. Raymond Y. Allis C.D. Bazett-Jones D.P. Th'ng J.P. J. Biol. Chem. 1998; 273: 24470-24478Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). this be the of the apoptotic cell histones and DNA be the of the heterochromatin and degradation from the perinuclear heterochromatin degraded the nuclear have not been to the of hyperacetylated histones in the apoptotic cell during early apoptosis prior to the hypoacetylated and trimethylated histone H4 this that no histones or DNA are from degradation this heterochromatin and degradation The of epigenetic modifications in histone and DNA during apoptosis and characterized by the methylation and acetylation of histone H4 from perinuclear heterochromatin and of DNA that these modifications may provide cells with the by the of specific nuclear specific or to the degradation of the nucleus in apoptosis and to chromatin condensation. with
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