Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging

Dale K. Shumaker, Thomas Dechat, Alexander Kohlmaier, Stephen A. Adam, Matthew R. Bozovsky, Michael R. Erdos, Maria Eriksson, Anne E. Goldman, Satya Khuon, Francis S. Collins, Thomas Jenuwein, Robert D. Goldman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

472 Scopus citations

Abstract

The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LAΔ50). Nuclei in cells expressing LAΔ50 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 1α (Hp1α) 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 LAΔ50 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.

Original languageEnglish (US)
Pages (from-to)8703-8708
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number23
DOIs
StatePublished - Jun 6 2006

Keywords

  • Heterochromatin
  • Histone methylation
  • Progeria

ASJC Scopus subject areas

  • General

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