Genomics

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


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. Hi-C was performed on three primary fibroblast cell lines: an HGPS patient (passage 17 and 19; HGPS), normal cells from the father of the HGPS patient (passage 18; Father), and age-matched normal cells (passage 20; Age Control).

ORGANISM(S): Homo sapiens  

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

PROVIDER: E-GEOD-41763 | ArrayExpress | 2012-10-30

SECONDARY ACCESSION(S): GSE41763SRP016586PRJNA178126

REPOSITORIES: GEO, ArrayExpress, ENA

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Publications

Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.

McCord Rachel Patton RP   Nazario-Toole Ashley A   Zhang Haoyue H   Chines Peter S PS   Zhan Ye Y   Erdos Michael R MR   Collins Francis S FS   Dekker Job J   Cao Kan K  

Genome research 20121114 2


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  ...[more]

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