RT Journal
A1 McCord, Rachel Patton
A1 Nazario-Toole, Ashley
A1 Zhang, Haoyue
A1 Chines, Peter S.
A1 Zhan, Ye
A1 Erdos, Michael R.
A1 Collins, Francis S.
A1 Dekker, Job
A1 Cao, Kan
T1 Correlated alterations in genome organization, histone methylation, and DNA–lamin A/C interactions in Hutchinson-Gilford progeria syndrome
JF Genome Research 
JO Genome Research 
YR 2013 
FD February 01 
VO 23 
IS 2 
SP 260 
OP 269 
DO 10.1101/gr.138032.112 
UL http://genome.cshlp.org/content/23/2/260.abstract 
AB 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.