Mapping of lamin A- and progerin-interacting genome regionsReport as inadecuate




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Chromosoma

, Volume 121, Issue 5, pp 447–464

First Online: 19 May 2012Received: 17 January 2012Revised: 23 April 2012Accepted: 26 April 2012

Abstract

Mutations in the A-type lamins A and C, two major components of the nuclear lamina, cause a large group of phenotypically diverse diseases collectively referred to as laminopathies. These conditions often involve defects in chromatin organization. However, it is unclear whether A-type lamins interact with chromatin in vivo and whether aberrant chromatin–lamin interactions contribute to disease. Here, we have used an unbiased approach to comparatively map genome-wide interactions of gene promoters with lamin A and progerin, the mutated lamin A isoform responsible for the premature aging disorder Hutchinson–Gilford progeria syndrome HGPS in mouse cardiac myoytes and embryonic fibroblasts. We find that lamin A-associated genes are predominantly transcriptionally silent and that loss of lamin association leads to the relocation of peripherally localized genes, but not necessarily to their activation. We demonstrate that progerin induces global changes in chromatin organization by enhancing interactions with a specific subset of genes in addition to the identified lamin A-associated genes. These observations demonstrate disease-related changes in higher order genome organization in HGPS and provide novel insights into the role of lamin–chromatin interactions in chromatin organization.

AbbreviationsAIREAutoimmune regulator

ANOVAOne-way analysis of variance

BACBacterial artificial chromosome

BPTFBromeodomain and plant homeo-domain transcription factor

ChIPChromatin immunoprecipitation

FDRFalse discovery rate

FPLDFamilial partial lipodystrophy

FCFold change

GTGene trap

GOGene ontology

GUCEGTF2IRD1 upstream control element

HAMLHuman acute myelogenous leukemia factor

HGPSHutchinson–Gilford progeria syndrome

INMInner nuclear membrane

IFNγInterferon gamma

LADLamin-associated domain

LMNALMNA knockout

MEFMouse embryonic fibroblast

NENuclear envelope

NPCNuclear pore complex

OLFROlfactory receptor

OST-AOne-STrEP tagged lamin A

OST-POne-STrEP tagged progerin

ONMOuter nuclear membrane

SF1Steroidogenic factor-1

TFTranscription factor

TFMTranscription factor motif

VMNRVomeronasal receptor

WTWild type

ZF10Zinc finger 10

Communicated by Erich Nigg

Electronic supplementary materialThe online version of this article doi:10.1007-s00412-012-0376-7 contains supplementary material, which is available to authorized users.

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Author: Nard Kubben - Michiel Adriaens - Wouter Meuleman - Jan Willem Voncken - Bas van Steensel - Tom Misteli

Source: https://link.springer.com/







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