Bystander gene activation by a locus control region

Abstract

Random assortment of genes within mammalian genomes establishes the potential for interference between neighboring genes with distinct transcriptional specificities. Long-range transcriptional controls further increase this potential. Exploring this problem is of fundamental importance to understanding gene regulation. In the human genome, the Igbeta (CD79b) gene is situated between the pituitary-specific human growth hormone (hGH) gene and its locus control region (hGH LCR). Igbeta protein is considered B-cell specific; its only known role is in B-cell receptor signaling. Unexpectedly, we found that hIgbeta is transcribed at high levels in the pituitary. This Igbeta transcription is dependent on pituitary-specific epigenetic modifications generated by the hGH LCR. In contrast, expression of Igbeta at its native site in B cells is independent of hGH LCR activity. These studies demonstrated that a gene with tissue-restricted transcriptional determinants (B cell) can be robustly activated in an unrelated tissue (pituitary) due to fortuitous positioning within an active chromatin domain. This 'bystander' gene activation pathway impacts on current concepts of tissue specificity and models of active chromatin domains.

Similar Transcriptomic Alterations in Cx43 Knockdown and Knockout Astrocytes

“…In addition to encoding proteins performing a wide diversity of functions (see below), the regulated genes in both Cx43 KO and SI astrocytes were located on all chromosomes as presented in Figure 2A. This lack of association of altered genes with a particular chromosome indicates that effects of both knockdown and knockout are not due to bystander effects related to chromosome location (see Cajiao et al, 2004) or "passenger effects" of the transgene construct (see Lusis et al 2007). …”

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

“…AS events that are not evolutionarily conserved are not necessarily unimportant as they may be specific to one organism and reflect the biology of that organism and/or might have evolved more recently and contributed to the diversification of species (Reddy, 2007). Once again, variable splicing ratios do not always imply functional importance (Hiller and Platzer, 2008), and the tissue-specific expression of a gene does not always imply a tissue-specific function (Cajiao et al, 2004). …”

Transcriptional interference – a crash course

“…the interference with chromosome replication in Saccharomyces cerevisiae as a result of transcription across its site of initiation [7]). We also exclude those cases of 'negative interference' whereby one transcriptional process, directly and in cis, enhances rather than suppresses a second transcriptional process, such as the fortuitous positioning of a gene within an active chromatin domain [8], chromatin remodelling that promotes intergenic transcription [9] and transcriptional coupling in which a promoter is activated by the activity of an upstream divergent promoter [10].…”

“…the interference with chromosome replication in Saccharomyces cerevisiae as a result of transcription across its site of initiation [7]). We also exclude those cases of 'negative interference' whereby one transcriptional process, directly and in cis, enhances rather than suppresses a second transcriptional process, such as the fortuitous positioning of a gene within an active chromatin domain [8], chromatin remodelling that promotes intergenic transcription [9] and transcriptional coupling in which a promoter is activated by the activity of an upstream divergent promoter [10].TI is often asymmetric and results from the existence of two promoters, the strong (aggressive) promoter reducing the expression of the weak (sensitive) promoter (Figure 1). These promoters can be either: (i) convergent promoters directing converging transcripts that overlap for at least part of their sequence ( Figure 1a); (ii) tandem promoters, one upstream of the other but transcribing in the same direction, with their transcripts possibly but not necessarily overlapping ( Figure 1b); or (iii) overlapping promoters, either divergent, convergent or tandem, in which the two RNAP-binding sites share at least a common DNA sequence (Figure 1c).…”