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.

Interallelic interaction and gene regulation in budding yeast

“…The first possibility is that the GAL1 promoter does not explore the whole nuclear space for binding partners, and the contacts it can make are restricted to a nuclear subvolume. Similar observations have been made in mammalian cells (4), and it was proposed that this constraint is imposed by the limited motion of the chromosomal context. The second possibility is that when the two reporters are at nonallelic sites, one or both of them can find better binding partners, preventing them from interacting with each other.…”

“…Three-dimensional (3D) organization of chromosomes also plays an important role in gene regulation. For example, distant cis-regulatory elements can be looped to the target promoters and regulate the corresponding genes, affecting both the average expression level and the cell-to-cell variability (1)(2)(3)(4). In yeast, promoters and terminators can form loops to allow rapid reactivation of the gene following a period of repression (5,6).…”

Conserved regulatory architecture underlies parallel genetic changes and convergent phenotypic evolution

“…However, at a larger scale, the functional organization of the whole svb regulatory region has been largely conserved. This higher order conservation is reminiscent of the structural conservation of Hox gene clusters (27), suggesting that long-range molecular interactions, such as enhancer-enhancer or enhancer-promoter interactions (28), constrain the evolution of large cis-regulatory regions, such as those found in svb and in Hox genes. In other words, the spacing and order of enhancers in the cis-regulatory region of svb might be crucial for the occurrence of precise physical contacts between different regulatory elements or between regulatory elements and the core promoter.…”

Are genes switched on when they kiss?

“…1 Chromosomal contact is strongly correlated with the transcriptional activity of interacting DNA elements. [2][3][4][5][6][7] Therefore, the physical contact between looped chromatin appears to be fundamental to gene regulation. However, whether the "kissing" of chromatin is a direct cause, or consequence, of transcription is a longstanding question in molecular biology and the subject of intense scrutiny.…”

“…9,11 In-depth analyses of chromatin interaction data sets reveal a large heterogeneity that infers significant cell-to-cell variability. 3,6 Thus, to decrypt the granularity of these events, the physical juxtaposition of interacting loci is verified at a single-cell level by fluorescent in situ hybridization (FISH). This microscopybased assay, which can target RNA or DNA (Table 1), reveals proximal FISH foci in a subset of the population.…”