title: Variegated gene expression caused by cell-specific long-range DNA interactions.
abstract: Mammalian genomes contain numerous regulatory DNA sites with unknown target genes. We used mice with an extra β-globin locus control region (LCR) to investigate how a regulator searches the genome for target genes. We find that the LCR samples a restricted nuclear subvolume, wherein it preferentially contacts genes controlled by shared transcription factors. No contacted gene is detectably upregulated except for endogenous β-globin genes located on another chromosome. This demonstrates genetically that mammalian trans activation is possible, but suggests that it will be rare. Trans activation occurs not pan-cellularly, but in 'jackpot' cells enriched for the interchromosomal interaction. Therefore, cell-specific long-range DNA contacts can cause variegated expression.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: Noordermeer
authors.forename: Elzo
authors.initials: E
authors.lastname: de Wit
authors.forename: Petra
authors.initials: P
authors.lastname: Klous
authors.forename: Harmen
authors.initials: H
authors.lastname: van de Werken
authors.forename: Marieke
authors.initials: M
authors.lastname: Simonis
authors.forename: Melissa
authors.initials: M
authors.lastname: Lopez-Jones
authors.forename: Bert
authors.initials: B
authors.lastname: Eussen
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.forename: Wouter
authors.initials: W
authors.lastname: de Laat
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D015870:Gene Expression; D017404:In Situ Hybridization, Fluorescence; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D019901:Locus Control Region; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D055544:beta-Globins / Q000235:genetics
chemical_list: D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D055544:beta-Globins; C080774:erythroid Kruppel-like factor; D004247:DNA