Title
Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome
UMMS Affiliation
Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Date
2-1-2013
Document Type
Article
Medical Subject Headings
Progeria; Nuclear Lamina; Heterochromatin; Nuclear Proteins
Disciplines
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Systems Biology
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.
Rights and Permissions
Citation: Genome Res. 2013 Feb;23(2):260-9. doi: 10.1101/gr.138032.112. Epub 2012 Nov 14. Link to article on publisher's site