title: The human beta-globin locus control region can silence as well as activate gene expression.
abstract: Using recombinase-mediated cassette exchange to test multiple transgenes at the same site of integration, we demonstrate a novel chromatin context-dependent silencer activity of the beta-globin locus control region (LCR). This silencer activity requires DNase I hypersensitive sites HS2 and HS3 but not HS4. After silencing, the silenced cassettes adopt a typical closed chromatin conformation (histone H3 and H4 deacetylation, histone H3-K4 methylation, DNA methylation, and replication in late S phase). In the absence of the LCR at the same site of integration, the chromatin remains decondensed. We demonstrate that the LCR is necessary but not sufficient to trigger these chromatin changes. We also provide evidence that this novel silencing activity is caused by transcriptional interference triggered by activation of transcription in the flanking sequences by the LCR.
authors.affiliation: Division of Hematology, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
authors.forename: Yong-Qing
authors.initials: YQ
authors.lastname: Feng
authors.forename: Renaud
authors.initials: R
authors.lastname: Warin
authors.forename: Taihao
authors.initials: T
authors.lastname: Li
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Olivier
authors.forename: Arnaud
authors.initials: A
authors.lastname: Besse
authors.forename: Amanda
authors.initials: A
authors.lastname: Lobell
authors.forename: Haiqing
authors.initials: H
authors.lastname: Fu
authors.forename: Chii Mei
authors.initials: CM
authors.lastname: Lin
authors.forename: Mirit I
authors.initials: MI
authors.lastname: Aladjem
authors.forename: Eric E
authors.initials: EE
authors.lastname: Bouhassira
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000235:genetics; D019175:DNA Methylation; D004261:DNA Replication / Q000235:genetics; D021901:DNA, Intergenic / Q000235:genetics; D020868:Gene Silencing; D005914:Globins / Q000235:genetics*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019901:Locus Control Region / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
chemical_list: D002843:Chromatin; D021901:DNA, Intergenic; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005914:Globins