Open Access Research article

A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing

Sylvain Meylan12, Anna C Groner12, Giovanna Ambrosini13, Nirav Malani4, Simon Quenneville12, Nadine Zangger12, Adamandia Kapopoulou12, Annamaria Kauzlaric12, Jacques Rougemont1, Angela Ciuffi5, Frederic D Bushman4, Philipp Bucher13 and Didier Trono12*

Author Affiliations

1 School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

2 Frontiers-in-Genetics National Center of Competence in Research, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

3 Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

4 Department of Microbiology, School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

5 Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

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BMC Genomics 2011, 12:378  doi:10.1186/1471-2164-12-378

Published: 26 July 2011

Abstract

Background

KRAB-ZFPs (Krüppel-associated box domain-zinc finger proteins) are vertebrate-restricted transcriptional repressors encoded in the hundreds by the mouse and human genomes. They act via an essential cofactor, KAP1, which recruits effectors responsible for the formation of facultative heterochromatin. We have recently shown that KRAB/KAP1 can mediate long-range transcriptional repression through heterochromatin spreading, but also demonstrated that this process is at times countered by endogenous influences.

Method

To investigate this issue further we used an ectopic KRAB-based repressor. This system allowed us to tether KRAB/KAP1 to hundreds of euchromatic sites within genes, and to record its impact on gene expression. We then correlated this KRAB/KAP1-mediated transcriptional effect to pre-existing genomic and chromatin structures to identify specific characteristics making a gene susceptible to repression.

Results

We found that genes that were susceptible to KRAB/KAP1-mediated silencing carried higher levels of repressive histone marks both at the promoter and over the transcribed region than genes that were insensitive. In parallel, we found a high enrichment in euchromatic marks within both the close and more distant environment of these genes.

Conclusion

Together, these data indicate that high levels of gene activity in the genomic environment and the pre-deposition of repressive histone marks within a gene increase its susceptibility to KRAB/KAP1-mediated repression.

Keywords:
KAP1; KRAB-zinc finger proteins; transcriptional repression; chromatin; heterochromatin; histone modifications