Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome
- Rachel McCord1,
- Ashley Nazario-Toole2,
- Haoyue Zhang2,
- Peter Chines3,
- Ye Zhan1,
- Michael Erdos3,
- Francis Collins3,
- Job Dekker1 and
- Kan Cao2,4
- 1 University of Massachusetts Medical School;
- 2 University of Maryland;
- 3 National Human Genome Research Institute, National Institutes of Health
- ↵* Corresponding author; email: kcao{at}umd.edu
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.
- Received February 16, 2012.
- Accepted October 29, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
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