Mutant Nuclear Lamin a Leads to Progressive Alterations of Epigenetic Control in Premature Aging

The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LA∆50). Nuclei in cells expressing LA∆50 are abnormally shaped and display a loss of heterochromatin. To determine the mechanisms responsible for the loss of heterochromatin, epigenetic marks regul...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-06, Vol.103 (23), p.8703-8708
Main Authors: Shumaker, Dale K., Dechat, Thomas, Kohlmaier, Alexander, Adam, Stephen A., Bozovsky, Matthew R., Erdos, Michael R., Eriksson, Maria, Goldman, Anne E., Khuon, Satya, Collins, Francis S., Jenuwein, Thomas, Goldman, Robert D.
Format: Article
Language:English
Subjects:
Aging
Aging, Premature - genetics
Aging, Premature - pathology
Biochemistry
Biological Sciences
Cell lines
Cell nucleus
Cell Nucleus - metabolism
Cells, Cultured
Cellular biology
Cellular immunity
Chromosomes
DNA Methylation
Epigenesis, Genetic
Female
HEK293 cells
HeLa Cells
Heterochromatin
Heterochromatin - metabolism
Histones
Histones - metabolism
Humans
Lamin Type A - genetics
Lamin Type A - metabolism
Lamins
Medicin och hälsovetenskap
Mutation - genetics
Nuclear lamina
Progeria - genetics
Recombinant Fusion Proteins - metabolism
RNA
RNA, Long Noncoding
RNA, Untranslated - genetics
Up-Regulation - genetics
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Summary:The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LA∆50). Nuclei in cells expressing LA∆50 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 la (Hpla) 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∆50 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0602569103