title: A gene-rich, transcriptionally active environment and the pre-deposition of repressive marks are predictive of susceptibility to KRAB/KAP1-mediated silencing.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Meylan
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ambrosini
authors.forename: Nirav
authors.initials: N
authors.lastname: Malani
authors.forename: Simon
authors.initials: S
authors.lastname: Quenneville
authors.forename: Nadine
authors.initials: N
authors.lastname: Zangger
authors.forename: Adamandia
authors.initials: A
authors.lastname: Kapopoulou
authors.forename: Annamaria
authors.initials: A
authors.lastname: Kauzlaric
authors.forename: Jacques
authors.initials: J
authors.lastname: Rougemont
authors.forename: Angela
authors.initials: A
authors.lastname: Ciuffi
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Philipp
authors.initials: P
authors.lastname: Bucher
authors.forename: Didier
authors.initials: D
authors.lastname: Trono
mesh_terms: D002843:Chromatin / Q000235:genetics; D020868:Gene Silencing; D023281:Genomics; D006367:HeLa Cells; D006657:Histones / Q000235:genetics; D006801:Humans; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D002843:Chromatin; D006657:Histones; D012097:Repressor Proteins; C422407:ZNF350 protein, human; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28