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

  1. Kan Cao2,4
  1. 1Program in Systems Biology, Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA;
  2. 2Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, USA;
  3. 3Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-8004, USA

    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 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.

    Footnotes

    • Received February 16, 2012.
    • Accepted October 29, 2012.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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