Transcriptional repression: conserved and evolved features

Abstract

The regulation of gene expression by transcriptional repression is an ancient and conserved mechanism that manifests itself in diverse ways. Here we summarize conserved pathways for transcriptional repression prevalent throughout all forms of life, as well as indirect mechanisms that appear to have originated in eukaryotes, consistent with the unique chromatin environment of eukaryotic genes. The direct interactions between transcriptional repressors and the core transcriptional machinery in bacteria and archaea are sufficient to generate a sophisticated suite of mechanisms that provide flexible control. These direct interactions contrast with the activity of corepressors, which provide an additional regulatory control in eukaryotes. Their modulation of chromatin structure represents an indirect pathway to downregulate transcription, and their diversity and modulation provide additional complexity suited to the requirements of elaborate eukaryotic repression patterns. New findings indicate that corepressors are not necessarily restricted to generating a single stereotypic output, but can rather exhibit diverse functional responses depending on the context in which they are recruited, providing a hitherto unsuspected additional source of diversity in transcriptional control. Mechanisms within eukaryotes appear to be highly conserved, with novel aspects chiefly represented by addition of lineage-specific corepressor scaffolds that provide additional opportunities for recruiting the same core machinery.

Figure 1. Distinct repression mechanisms used by prokaryotic and eukaryotic repressors

A) Bacterial repressors (R) directly target the core transcription machinery in the following stages: i) repressors bind to the promoter proximal sites to block the binding of RNA polymerase (Pol); ii) and iii) repressors bind simultaneously to the promoter with RNA polymerase, inhibiting its transition from closed to open complex, or preventing promoter escape; iv) inhibition of RNA polymerase promoter escape can also occur when repressors bind 3′ of the initiation site. B) Due to the increased genome complexity and presence of chromatin, eukaryotic repressors (R) rely largely on recruitment of corepressors and chromatin modifying enzymes, including HMTs (histone methyltransferases), HDACs (histone deacetylases), KDMs (lysine demethylases) and chromatin remodeling factors with ATPase activity. In some cases these corepressors interact directly with activators (A) or the basal machinery.

Figure 2. Modulation of corepressor activity through posttranslational modification and small molecules

A) Subcellular localization of corepressors is affected by posttranslational modifications, such as phosphorylation, SUMOylation or acetylation. B) Posttranslational modifications of corepressors alter a protein-protein interaction surface, either inhibiting or enhancing the recruitment of corepressors. C) Binding to cellular compounds may impact the corepressor activity: CtBP is suggested to be a more potent corepressor when bound to NADH compared to NAD+, thus allowing it to function as a cellular redox state sensor

Figure 3. Possible mechanisms underlying Groucho-mediated context-dependent repression

A) Groucho adopts alternative conformations when associated with different repressors, and only spreads when recruited by long-range repressors. B) Groucho is associated with distinct corepressor complexes that are recruited by different repressors; a form that is capable of spreading is recruited by long-range repressors.