Variegated gene expression caused by cell-specific long-range DNA interactions

D. Noordermeer, E. de Wit, P. Klous, H. van de Werken, M. Simonis, M. Lopez-Jones, B. Eussen, A.M. Klein, R.H. Singer, W. de Laat

Research output: Contribution to journal/periodicalArticleScientificpeer-review

127 Citations (Scopus)


Mammalian genomes contain numerous regulatory DNA sites with unknown target genes. We used mice with an extra beta-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 beta-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. [KEYWORDS: Animals, DNA/ genetics/ metabolism, GATA1 Transcription Factor/metabolism, Gene Expression, In Situ Hybridization, Fluorescence, Kruppel-Like Transcription Factors/metabolism, Locus Control Region, Mice, Mice, Transgenic, RNA, Messenger/genetics/metabolism, Transcriptional Activation, beta-Globins/genetics]
Original languageEnglish
Pages (from-to)944-951
JournalNature Cell Biology
Issue number8
Publication statusPublished - 2011


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