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

ABSTRACT: Mammalian genomes contain numerous DNA elements with potential transcription regulatory function but unknown target genes. We used transgenic, gain-of-function mice with an ectopic copy of the beta-globin locus control region (LCR) to better understand how regulatory elements dynamically search the genome for target genes. We find that the LCR samples a restricted nuclear sub-volume in which it forms preferential contacts with genes controlled by shared transcription factors. One contacted gene, betah1, located on another chromosome, is upregulated, providing genetic demonstration that mammalian enhancers can function between chromosomes. Upregulation is not pan-cellular but confined to selected ‘jackpot’ cells significantly enriched for inter-chromosomal LCR-betah1 interactions. This implies that long-range DNA contacts are relatively stable and cell-specific and, when functional, cause variegated expression. We refer to this as spatial effect variegation (SEV). The data provide a dynamic and mechanistic framework for enhancer action, important for assigning function to the one- and three-dimensional structure of DNA. A knock-in mouse strain was compared to a wild-type FVB strain. The knock-in mouse strain carries a human beta-globin LCR in the Rad23a locus. We performed 4C for the Rad23a locus in the knock-in and the wild-type strain. Biological replicates were analyzed in a reversed dye orientation. At the RNA level these mice were characterized with Affymetrix expression arrays. We analyzed three biological replicates for the WT and the knock-in.

ORGANISM(S): Mus musculus

SUBMITTER: Elzo de Wit 

PROVIDER: E-GEOD-24614 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress