Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Progeria; Nuclear Lamina; Heterochromatin; Nuclear Proteins
Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetics and Genomics | Systems Biology
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.
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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
McCord, Rachel Patton; Nazario-Toole, Ashley; Zhang, Haoyue; Chines, Peter; Zhan, Ye; Erdos, Michael; Collins, Francis; Dekker, Job; and Cao, Kan, "Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome" (2013). Program in Systems Biology Publications and Presentations. 16.