title: Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context-dependent manner.
abstract: Locus control regions (LCRs) are gene regulatory elements in mammals that can overcome the highly repressive effects normally associated with heterochromatic transgene locations (for example the centromere) in mice. Deletion of essential LCR sequences renders the cognate gene susceptible to this form of repression, so a proportion of the cells from transgenic mice that would normally express the transgene are silenced-a phenomenon known as position effect variegation (PEV). We show here that PEV can also occur when the transgene is non-centromeric and that the extent of variegation can be developmentally regulated. Furthermore, by overexpressing a mammalian homologue (M31) of Drosophila melanogaster heterochromatin protein 1 (HP1; refs 7,8) in transgenic mouse lines that exhibit PEV, it is possible to modify the proportion of cells that silence the transgene in a dose-dependent manner. Thus, we show M31 overexpression to have two contrasting effects which are dependent on chromosomal context: (i) it enhanced PEV in those lines with centromeric or pericentromeric transgene locations; and (ii) it suppressed PEV when the transgene was non-centromeric. Our results indicate that components or modifiers of heterochromatin may have a chromosomal-context-dependent role in gene silencing and activation decisions in mammals.
authors.affiliation: Division of Molecular Immunology, National Institute for Medical Research, London, UK. r-festen@nimr.mrc.ac.uk
authors.forename: R
authors.initials: R
authors.lastname: Festenstein
authors.forename: S
authors.initials: S
authors.lastname: Sharghi-Namini
authors.forename: M
authors.initials: M
authors.lastname: Fox
authors.forename: K
authors.initials: K
authors.lastname: Roderick
authors.forename: M
authors.initials: M
authors.lastname: Tolaini
authors.forename: T
authors.initials: T
authors.lastname: Norton
authors.forename: A
authors.initials: A
authors.lastname: Saveliev
authors.forename: D
authors.initials: D
authors.lastname: Kioussis
authors.forename: P
authors.initials: P
authors.lastname: Singh
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018801:CD2 Antigens / Q000235:genetics; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006570:Heterochromatin / Q000235:genetics; D006801:Humans; D019901:Locus Control Region; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D018801:CD2 Antigens; C096188:Cbx1 protein, mouse; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D000090266:Chromobox Protein Homolog 5