Document Detail


Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.
MedLine Citation:
PMID:  23152449     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Rachel Patton McCord; Ashley Nazario-Toole; Haoyue Zhang; Peter S Chines; Ye Zhan; Michael R Erdos; Francis S Collins; Job Dekker; Kan Cao
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't     Date:  2012-11-14
Journal Detail:
Title:  Genome research     Volume:  23     ISSN:  1549-5469     ISO Abbreviation:  Genome Res.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-04     Completed Date:  2013-07-15     Revised Date:  2014-04-08    
Medline Journal Info:
Nlm Unique ID:  9518021     Medline TA:  Genome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  260-9     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE41764
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MeSH Terms
Descriptor/Qualifier:
Cell Line
Chromatin Immunoprecipitation
Fibroblasts / metabolism
Gene Expression Regulation
Genome, Human*
Heterochromatin / metabolism
Histones / metabolism*
Humans
Lamins / metabolism*
Methylation
Progeria / genetics*,  metabolism*
Protein Binding
Sequence Analysis, DNA
Grant Support
ID/Acronym/Agency:
F32 GM100617/GM/NIGMS NIH HHS; F32GM100617/GM/NIGMS NIH HHS; HG003143/HG/NHGRI NIH HHS; R00 AG029761/AG/NIA NIH HHS; R00AG029761/AG/NIA NIH HHS; T32 AI089621/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Heterochromatin; 0/Histones; 0/Lamins
Comments/Corrections

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