title: Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome.
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.
authors.affiliation: Program in Systems Biology, Department of Biochemistry and Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
authors.forename: Rachel Patton
authors.initials: RP
authors.lastname: McCord
authors.forename: Ashley
authors.initials: A
authors.lastname: Nazario-Toole
authors.forename: Haoyue
authors.initials: H
authors.lastname: Zhang
authors.forename: Peter S
authors.initials: PS
authors.lastname: Chines
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Erdos
authors.forename: Francis S
authors.initials: FS
authors.lastname: Collins
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.forename: Kan
authors.initials: K
authors.lastname: Cao
mesh_terms: D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D015894:Genome, Human; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D034882:Lamins / Q000378:metabolism*; D008745:Methylation; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D017422:Sequence Analysis, DNA
chemical_list: D006570:Heterochromatin; D006657:Histones; D034882:Lamins