KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading.

Détails

Ressource 1Télécharger: BIB_C24753BC493E.P001.pdf (938.15 [Ko])
Etat: Serval
Version: Final published version
ID Serval
serval:BIB_C24753BC493E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
KRAB-zinc finger proteins and KAP1 can mediate long-range transcriptional repression through heterochromatin spreading.
Périodique
Plos Genetics
Auteur(s)
Groner A.C., Meylan S., Ciuffi A., Zangger N., Ambrosini G., Dénervaud N., Bucher P., Trono D.
ISSN
1553-7404 (Electronic)
ISSN-L
1553-7390
Statut éditorial
Publié
Date de publication
03/2010
Peer-reviewed
Oui
Volume
6
Numéro
3
Pages
e1000869
Langue
anglais
Notes
Publication types: Journal Article
Résumé
Krüppel-associated box domain-zinc finger proteins (KRAB-ZFPs) are tetrapod-specific transcriptional repressors encoded in the hundreds by the human genome. In order to explore their as yet ill-defined impact on gene expression, we developed an ectopic repressor assay, allowing the study of KRAB-mediated transcriptional regulation at hundreds of different transcriptional units. By targeting a drug-controllable KRAB-containing repressor to gene-trapping lentiviral vectors, we demonstrate that KRAB and its corepressor KAP1 can silence promoters located several tens of kilobases (kb) away from their DNA binding sites, with an efficiency which is generally higher for promoters located within 15 kb or less. Silenced promoters exhibit a loss of histone H3-acetylation, an increase in H3 lysine 9 trimethylation (H3K9me3), and a drop in RNA Pol II recruitment, consistent with a block of transcriptional initiation following the establishment of silencing marks. Furthermore, we reveal that KRAB-mediated repression is established by the long-range spreading of H3K9me3 and heterochromatin protein 1 beta (HP1beta) between the repressor binding site and the promoter. We confirm the biological relevance of this phenomenon by documenting KAP1-dependent transcriptional repression at an endogenous KRAB-ZFP gene cluster, where KAP1 binds to the 3' end of genes and mediates propagation of H3K9me3 and HP1beta towards their 5' end. Together, our data support a model in which KRAB/KAP1 recruitment induces long-range repression through the spread of heterochromatin. This finding not only suggests auto-regulatory mechanisms in the control of KRAB-ZFP gene clusters, but also provides important cues for interpreting future genome-wide DNA binding data of KRAB-ZFPs and KAP1.
Mots-clé
Acetylation, Base Pairing, Binding Sites, Cell Line, Chromosomal Proteins, Non-Histone/metabolism, Gene Silencing, Heterochromatin/metabolism, Histones/metabolism, Humans, Methylation, Promoter Regions, Genetic/genetics, RNA Polymerase II/metabolism, Repressor Proteins/metabolism, Transcription, Genetic, Zinc Fingers
Pubmed
Web of science
Open Access
Oui
Création de la notice
07/02/2011 10:55
Dernière modification de la notice
09/05/2019 0:49
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