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

Comments

© 2013, Published by Cold Spring Harbor Laboratory Press

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

Related Resources

Link to Article in PubMed

Journal Title

Genome research

PubMed ID

23152449

 
 

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