Regulation of gene expression by transcriptional repression represents an ancient and conserved mechanism that manifests itself in diverse forms. 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 their unique chromatin environment. The direct interactions between transcriptional repressors and core 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 provides 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.

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The insulin receptor gene encodes an evolutionarily conserved signaling protein with a wide spectrum of functions in metazoan development. The insulin signaling pathway plays key roles in processes such as metabolic regulation, growth control, and neuronal function. Misregulation of the pathway features in diabetes, cancer, and neurodegenerative diseases, making it an important target for clinical interventions. While much attention has been focused on differential pathway activation through ligand availability, sensitization of overall signaling may also be mediated by differential expression of the insulin receptor itself. Although first characterized as a “housekeeping” gene with stable expression, comparative studies have shown that expression levels of the human INSR mRNA differ by tissue and in response to environmental signals. Our recent analysis of the transcriptional controls affecting expression of the Drosophila insulin receptor gene indicates that a remarkable amount of DNA is dedicated to encoding sophisticated feedback and feed forward signals. The human INSR gene is likely to contain a similar level of transcriptional complexity; here, we summarize over three decades of molecular biology and genetic research that points to a still incompletely understood regulatory control system. Further elucidation of transcriptional controls of INSR will provide the basis for understanding human genetic variation that underlies population-level physiological differences and disease.

Despite the pervasive roles for repressors in transcriptional control, the range of action of these proteins on cis regulatory elements remains poorly understood. Knirps has essential roles in patterning the Drosophila embryo by means of short-range repression, an activity that is essential for proper regulation of complex transcriptional control elements. Short-range repressors function in a local fashion to interfere with the activity of activators or basal promoters within Ϸ100 bp. In contrast, long-range repressors such as Hairy act over distances >1 kb. The functional distinction between these two classes of repressors has been suggested to stem from the differential recruitment of the CtBP corepressor to short-range repressors and Groucho to long-range repressors. Contrary to this differential recruitment model, we report that Groucho is a functional part of the Knirps short-range repression complex. The corepressor interaction is mediated via an eh-1 like motif present in the N terminus and a conserved region present in the central portion of Knirps. We also show that this interaction is important for the CtBP-independent repression activity of Knirps and is required for regulation of even-skipped. Our study uncovers a previously uncharacterized interaction between proteins previously thought to function in distinct repression pathways, and indicates that the Groucho corepressor can be differentially harnessed to execute short-and long-range repression. S hort-range transcriptional repression has a central role in development, and perhaps nowhere have the molecular workings of eukaryotic developmental gene networks been more extensively analyzed than in the Drosophila blastoderm embryo. Here, both transcriptional activators and repressors transduce temporal and spatial information into characteristic patterns of gene expression essential for development. Repressors have key parts in this process, evidenced by the central position in the hierarchy of genes such as hairy, giant, knirps (kni), and Kruppel, all of which function as dedicated repressors. Transcriptional repressors have been characterized based on their range of action; short-range repressors such as Knirps work over distances of Ͻ100 bp to quench activators or basal promoters (1). In contrast, long-range repressors such as Hairy function over distances of 1 kb to silence their target genes in a process suggested to involve extensive spreading of a recruited corepressor, Groucho (2, 3).Seminal work in this area by the Levine laboratory has prompted the suggestion that the functional differences in the range of action of the two classes of repressors reflect the recruiting of distinct corepressors (4). Short-range repressors such as Knirps, Kruppel, Giant, and Snail associate with the C-terminal binding protein (CtBP) corepressor, whereas Groucho is implicated in mediating long-range repression by Hairy (4, 5). Both evolutionarily conserved corepressors have been linked to chromatin-modifying enzymes, and each associates with sequence-specific D...

Quantitative measurements of the Hunchback transcription factor in Drosophila embryos show that its target genes can respond with a high degree of precision to the exact level of the protein, simulating a continuous, analog readout, while other target genes show a combinatorial effect, resembling a Boolean logic element.