Transcriptional Silencers: Driving Gene Expression with the Brakes On

Abstract

Silencers are regulatory DNA elements that reduce transcription from their target promoters; they are the repressive counterparts of enhancers. Although discovered decades ago, and despite evidence of their importance in development and disease, silencers have been much less studied than enhancers. Recently, however, a series of papers have reported systematic studies of silencers in various model systems. Silencers are often bifunctional regulatory elements that can also act as enhancers, depending on cellular context, and are enriched for expression quantitative trait loci (eQTLs) and disease-associated variants. There is not yet evidence of a 'silencer chromatin signature', in the distribution of histone modifications or associated proteins, that is common to all silencers; instead, silencers may fall into various subclasses, acting by distinct (and possibly overlapping) mechanisms.

Keywords: chromatin; repression; silencer; transcriptional gene regulation.

Figure 1.. Silencers can fine-tune gene expression patterns.

(A) Silencers can create complexity and specificity in spatial expression driven by more broadly acting enhancers. (B) Silencers can fine-tune temporal expression patterns by opposing the activity of enhancers activated in a parent cell lineage. (C) Silencers can reduce promoter activity to establish cell type-specific expression levels.

Figure 2.. Techniques used to identify silencers.

(A) In a silencer reporter assay, an easily measured ectopic “reporter” gene is expressed under the control of a minimal promoter and appropriate enhancer. A sequence to be tested for silencer activity is added and compared to a no-silencer control. Silencer activity can be detected by measurement of reporter gene expression in cultured cells (B), or visualization of the resulting expression pattern in transgenic organisms (C). (D) Silencer activity of a sequence element in its native genomic context can be assayed by targeted deletion and measurement of the resulting expression of potential target genes.

Figure 3.. Potential mechanisms of silencers.

(A) Silencers, particularly those bound by Snail in Drosophila embryonic mesoderm, can disrupt promoter-enhancer interactions in order to dampen expression. (B) Silencers may harbor TF binding sites that overlap sites for activators, such that the binding of certain TFs can disrupt the induction of transcription. This is particularly relevant for bifunctional cis-regulatory elements that can function as silencers and promoters depending on context. (C) Transcription of intragenic enhancers can interfere with the passage of RNA polymerase (green) through their host genes, attenuating their expression while activating transcription of distal genes. (D) Silencers might act at a distance to deposit repressive histone marks (red circles) and/or proteins that facilitate local compaction, such as HP1 or Polycomb repressive complexes. (E) Alternatively, the silencer may nucleate the spread of heterochromatin via Polycomb or HP1 that is propagated across the target gene.