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The Streptococcus pneumoniae fatty acid synthesis (FAS) pathway is globally controlled at the transcriptional level by the repressor FabT and its co-repressor acyl carrier protein (acyl-ACP), the intermediate of phospholipid synthesis. Here, we report the crystal structure of FabT complexed with a 23-bp dsDNA, which indicates that FabT is a weak repressor with low DNA-binding affinity in the absence of acyl-ACP. Modification of ACP with a long-chain fatty acid is necessary for the formation of a stable complex with FabT, mimicked in vitro by cross-linking, which significantly elevates the DNA-binding affinity of FabT. Altogether, we propose a putative working model of gene repression under the double control of FabT and acyl-ACP, elucidating a distinct repression network for Pneumococcus to precisely coordinate FAS.

The transcription factor Myocyte enhancer factor 2C (MEF2C) plays a key role in the late differentiation of skeletal muscle progenitor cells, the so-called myoblasts. During myoblast differentiation, both MEF2C expression and transcriptional activity are regulated. We have reported that nTRIP6, the nuclear isoform of the focal adhesion LIM domain protein TRIP6, acts as an adaptor transcriptional co-activator for several transcription factors. It interacts with the promoter-bound transcription factors and consequently mediates the recruitment of other co-activators. Based on a described interaction between MEF2C and TRIP6 in a yeast-two-hybrid screen, we hypothesised a co-regulatory function of nTRIP6 for MEF2C. In proliferating myoblasts, nTRIP6 interacted with MEF2C and was recruited together with MEF2C to the MEF2-binding regions of the MEF2C target genes Myom2, Mb, Tnni2 and Des. Silencing nTRIP6 or preventing its interaction with MEF2C increased MEF2C transcriptional activity and increased the expression of these MEF2C target genes. Thus, nTRIP6 acts as a co-repressor for MEF2C. Mechanistically, nTRIP6 mediated the recruitment of the class IIa histone deacetylase HDAC5 to the MEF2C-bound promoters. In conclusion, our results unravel a transcriptional co-repressor function for nTRIP6. This adaptor co-regulator can thus exert either co-activator or co-repressor functions, depending on the transcription factor it interacts with.

Dentatorubral-pallidoluysian atrophy is a polyglutamine disorder caused by expansion of a CAG repeat tract within the human atrophin 1 gene. Truncated fragments of polyQ Atrophin one accumulate in neuronal nuclei of DRPLA patients and represent the toxic form. The normal Atrophin 1 protein is conserved from Drosophila to mammals where it acts as transcriptional co-repressor.

The development and coordination of complex tissues in eukaryotes requires precise spatial control of fate-specifying genes. Although investigations of such control have traditionally focused on mechanisms of transcriptional activation, transcriptional repression has emerged as being equally important in the establishment of gene expression territories. In the angiosperm flower, specification of lateral organ fate relies on the spatial regulation of the ABC floral organ identity genes. Our understanding of how the boundaries of these expression domains are controlled is not complete. Here, we report that the A-class organ identity gene APETALA2 (AP2), which is known to repress the C-class gene AGAMOUS, also regulates the expression borders of the B-class genes APETALA3 and PISTILLATA, and the E-class gene SEPALLATA3. We show that AP2 represses its target genes by physically recruiting the co-repressor TOPLESS and the histone deacetylase HDA19. These results demonstrate that AP2 plays a broad role in flower development by controlling the expression domains of numerous floral organ identity genes.

In the version of this Article originally published, in Fig. 2c, the '+' sign and 'OSKM' were superimposed in the label '+OSKM'. In Fig. 4e, in the labels, all instances of 'Ant' should have been 'Anti-'. And, in Fig. 7a, the label '0.0' was misplaced; it should have been on the colour scale bar. These figures have now been corrected in the online versions.

Gene expression is often controlled by transcriptional repressors during development. Many transcription factors lack intrinsic repressive activity but recruit co-factors that inhibit productive transcription. Here we discuss new insights and models for repression mediated by the Groucho/Transducin-Like Enhancer of split (Gro/TLE) family of co-repressor proteins.

A multitude of post-translational modifications take place on histones, one of the best studied being acetylation on lysine residues, which is generally associated with gene activation. During the last decades, several so-called co-repressor protein complexes that carry out the reverse process, histone deacetylation, have been identified and characterized, such as the Sin3, N-CoR/SMRT and NuRD complexes. Although a repressive role for these complexes in regulating gene expression is well established, accumulating evidence also points to a role in gene activation. Here, we argue that integration of various state-of-the-art technologies, addressing different aspects of transcriptional regulation, is essential to unravel this apparent biological versatility of 'co-repressor' complexes.

As the common signal transducer for IL-6 family cytokines, gp130 interacts with various signal molecules. Our previous work found the amino-terminal enhancer of split (AES) molecule interacts with gp130 intracellular region through its conserved glutamine-rich (Q) domain. The Q domain in AES shares high homology with those in the transcription co-repressor transducin-like enhancer of split (TLE) proteins. The yeast two-hybrid assay, gluthione S-transferase fusion protein pull-down assay and immuno-co-precipitation assay indicated that the Q domain of TLE1 is capable of binding gp130 intracellular domain, and the intracellular membrane proximal region of gp130 containing conserved Box1 and Box2 motifs seemed essential for this interaction. The interaction between gp130 and TLE1 indicated that molecules of TLE family might play a role in gp130 signaling.

Exciting new observations about receptor-interacting and nuclear accessory proteins and their ability to regulate gene expression have provided insight into hormonal regulation of gene expression. The goal of a recent NIDDK workshop was to discuss how diverse signaling pathways could converge on target genes and provide regulatory input to either activate or repress transcription.

A central issue in mediating repression by nuclear hormone receptors is the distinct or redundant function between co-repressors N-CoR (nuclear receptor co-repressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptor). To address the functional relationship between SMRT and N-CoR in TR (thyroid hormone receptor)-mediated repression, we have identified multiple TR target genes, including BCL3 (B-cell lymphoma 3-encoded protein), Spot14 (thyroid hormone-inducible hepatic protein), FAS (fatty acid synthase), and ADRB2 (β-adrenergic receptor 2). We demonstrated that siRNA (small interfering RNA) treatment against either N-CoR or SMRT is sufficient for the de-repression of multiple TR target genes. By the combination of sequence mining and physical association as determined by ChIP (chromatin immunoprecipitation) assays, we mapped the putative TREs (thyroid hormone response elements) in BCL3, Spot14, FAS and ADRB2 genes. Our data clearly show that SMRT and N-CoR are independently recruited to various TR target genes. We also present evidence that overexpression of N-CoR can restore repression of endogenous genes after knocking down SMRT. Finally, unliganded, co-repressor-free TR is defective in repression and interacts with a co-activator, p300. Collectively, these results suggest that both SMRT and N-CoR are limited in cells and that knocking down either of them results in co-repressor-free TR and consequently de-repression of TR target genes.

Photoreceptor cell-specific nuclear receptor (PNR) (NR2E3) acts as a sequence-specific repressor that controls neuronal differentiation in the developing retina. We identified a novel PNR co-repressor, Ret-CoR, that is expressed in the developing retina and brain. Biochemical purification of Ret-CoR identified a multiprotein complex that included E2F/Myb-associated proteins, histone deacetylases (HDACs) and NCoR/HDAC complex-related components. Ret-CoR appeared to function as a platform protein for the complex, and interacted with PNR via two CoRNR motifs. Purified Ret-CoR complex exhibited HDAC activity, co-repressed PNR transrepression function in vitro, and co-repressed PNR function in PNR target gene promoters, presumably in the retinal progenitor cells. Notably, the appearance of Ret-CoR protein was cell-cycle-stage-dependent (from G1 to S). Therefore, Ret-CoR appears to act as a component of an HDAC co-repressor complex that supports PNR repression function in the developing retina, and may represent a co-regulator class that supports transcriptional regulator function via cell-cycle-dependent expression.

Using Western blot analysis we found transcriptional co-repressor Sin3A to be expressed at a higher level in male mouse kidney than in females. HDAC1 (histone deacetylase 1) protein, another co-repressor forming complexes with Sin3A, was not higher in males. No sex differences in Sin3A expression were found after gonadectomy, suggesting that gonadal secretions in adulthood cause the sex difference in kidney expression of Sin3A. In contrast, HDAC1 levels were higher in castrated gonadal males than in females, which presumably reflects a long-lasting differentiating effect of testicular secretions in early development on this protein in kidneys. In gonadectomized mice in which sex chromosome complement (XX vs. XY) is independent of gonadal type (testes vs. ovaries), there was no difference in the level of Sin3A or HDAC1 expression in kidney in XX or XY mice of the same gonadal sex.

Many cases of acute myelogenous leukemia (AML) are characterized by non-random chromosomal translocations that fuse a DNA-binding protein with a transcriptional regulator, which in turn may aberrantly recruit a co-repressor complex. The similarities in this pattern between different AML chimeric fusions have led to a paradigm that stresses the importance of the co-repressor complex in altering the pattern of expression of genes targeted by the DNA-binding moiety of the fusion. Such findings beg the question of whether the fusion proteins merely serve as anchors to recruit the co-repressor complex or whether they play other significant roles in leukemogenesis. The answers to this question may have therapeutic importance since we now have the ability to target various components of the co-repressor complex, such as the histone deacetylase (HDAC) enzymes. In this Prospect, we wish to highlight some of the complexities and difficulties with the existing molecular paradigm of this challenging group of disorders.

Univ Minnesota, Dept Genet Cell Biol & Dev, Biol Sci Ctr 250, St Paul, MN 55108 USA; Univ Minnesota, Arnold & Mabel Beckman Ctr TRansposon Res, St Paul, MN 55108 USA; Chinese Acad Sci, Inst Hydrobiol, Wuhan, Peoples R China; Discovery Genom Inc, St Paul, MN USA

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