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

TY - JOUR

T1 - Variegated gene expression caused by cell-specific long-range DNA interactions

AU - Noordermeer, D.

AU - de Wit, E.

AU - Klous, P.

AU - van de Werken, H.

AU - Simonis, M.

AU - Lopez-Jones, M.

AU - Eussen, B.

AU - Klein, A.M.

AU - Singer, R.H.

AU - de Laat, W.

N1 - Reporting year: 2011 Metis note: 3151580;

PY - 2011

Y1 - 2011

N2 - 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]

AB - 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]

U2 - 10.1038/ncb2278

DO - 10.1038/ncb2278

M3 - Article

SN - 1465-7392

VL - 13

SP - 944

EP - 951

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -