{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T19:51:54Z","timestamp":1792439514011,"version":"4.5.0"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"23","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2006,6,6]]},"abstract":"<jats:p>The premature aging disease Hutchinson\u2013Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LA\u039450). Nuclei in cells expressing LA\u039450 are abnormally shaped and display a loss of heterochromatin. To determine the mechanisms responsible for the loss of heterochromatin, epigenetic marks regulating either facultative or constitutive heterochromatin were examined. In cells from a female HGPS patient, histone H3 trimethylated on lysine 27 (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive X chromosome (Xi). The methyltransferase responsible for this mark, EZH2, is also down-regulated. These alterations are detectable before the changes in nuclear shape that are considered to be the pathological hallmarks of HGPS cells. The results also show a down-regulation of the pericentric constitutive heterochromatin mark, histone H3 trimethylated on lysine 9, and an altered association of this mark with heterochromatin protein 1\u03b1 (Hp1\u03b1) and the CREST antigen. This loss of constitutive heterochromatin is accompanied by an up-regulation of pericentric satellite III repeat transcripts. In contrast to these decreases in histone H3 methylation states, there is an increase in the trimethylation of histone H4K20, an epigenetic mark for constitutive heterochromatin. Expression of LA\u039450 in normal cells induces changes in histone methylation patterns similar to those seen in HGPS cells. The epigenetic changes described most likely represent molecular mechanisms responsible for the rapid progression of premature aging in HGPS patients.<\/jats:p>","DOI":"10.1073\/pnas.0602569103","type":"journal-article","created":{"date-parts":[[2006,5,31]],"date-time":"2006-05-31T20:44:56Z","timestamp":1149108296000},"page":"8703-8708","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":735,"title":["Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging"],"prefix":"10.1073","volume":"103","author":[{"given":"Dale K.","family":"Shumaker","sequence":"first","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Dechat","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Kohlmaier","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen A.","family":"Adam","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Bozovsky","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Erdos","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Eriksson","sequence":"additional","affiliation":[{"name":"Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Halsovagen 7, Hiss E, Plan 6, 141 57 Huddinge, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E.","family":"Goldman","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satya","family":"Khuon","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis S.","family":"Collins","sequence":"additional","affiliation":[{"name":"National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jenuwein","sequence":"additional","affiliation":[{"name":"Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Goldman","sequence":"additional","affiliation":[{"name":"*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2006,6,6]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402943101"},{"key":"e_1_3_3_2_2","first-page":"473","volume":"69","author":"Hutchinson J.","year":"1886","unstructured":"J. Hutchinson Medicochir. Trans. 69, 473\u2013477 (1886).","journal-title":"Medicochir. Trans."},{"key":"e_1_3_3_3_2","first-page":"188","volume":"73","author":"Gilford M.","year":"1904","unstructured":"M. Gilford Practitioner. 73, 188\u2013217 (1904).","journal-title":"Practitioner."},{"key":"e_1_3_3_4_2","first-page":"243","volume":"87","author":"Stables G. I.","year":"1994","unstructured":"G. I. Stables, W. N. Morley J. R. Soc. Med. 87, 243\u2013244 (1994).","journal-title":"J. R. Soc. Med."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084125"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01629"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.960502"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.08.093"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1006\/jsbi.1998.3987"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(03)00050-4"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1550"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2005.00447.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1567"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2003.09.007"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.142.1.13"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80248-8"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0020171"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506001102"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1204"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1076997"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(03)00477-5"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/35065132"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.9002.S216"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00542-6"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e03-07-0487"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.5.1695"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.300704"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0511133103"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R500011-JLR200"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.24.12.5475-5484.2004"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200306104"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205166200"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/227680a0"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1177\/002215549704501201"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0602569103","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T14:50:59Z","timestamp":1649775059000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0602569103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,6,6]]},"references-count":34,"journal-issue":{"issue":"23","published-print":{"date-parts":[[2006,6,6]]}},"alternative-id":["10.1073\/pnas.0602569103"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0602569103","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1001213.374807","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,6,6]]},"assertion":[{"value":"2006-06-06","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}