Transcriptomics

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Correlated alterations in genome organization, histone methylation, and DNA-lamina interactions in Hutchinson-Gilford progeria syndrome (expression)


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 HGPS cells experience genome-wide alterations in patterns of H3K27me3 deposition, changes in the associations of genomic loci with nuclear lamin A/C, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains that characterizes chromosome folding in normal cells. 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 then lead to the genomic disorganization and changes in transcriptional regulation we observe in HGPS fibroblasts. We analyzed gene expression of primary fibroblasts of a Hutchinson-Gilford progeria syndrome patient, a healthy age-matched control, and the patient's healthy father using the Affymetrix GeneChip Human Genome U133 Plus 2.0 Array platform. Arrays were filtered and normalized using RMA. Two replicates were performed.

ORGANISM(S): Homo sapiens  

SUBMITTER: Haoyue Zhang  Rachel P McCord   Ashley Nazario-Toole   Francis S Collins   Michael R Erdos   Peter S Chines   Job Dekker   Kan Cao   Ye Zhan   Rachel Patton McCord    

PROVIDER: E-GEOD-41751 | ArrayExpress | 2012-10-30

SECONDARY ACCESSION(S): GSE41751PRJNA178124

REPOSITORIES: GEO, ArrayExpress

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