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PubMed2002

The many faces of histone lysine methylation.

Diverse post-translational modifications of histone amino termini represent an important epigenetic mechanism for the organisation of chromatin structure and the regulation of gene activity. Within the past two years, great progress has been made in understanding the functional implications of histone methylation; in particular through the characterisation of histone methyltransferases that direct the site-specific methylation of, for example, lysine 9 and lysine 4 positions in the histone H3 amino terminus. All known histone methyltransferases of this type contain the evolutionarily conserved SET domain and appear to be able to stimulate either gene repression or gene activation. Methylation of H3 Lys9 and Lys4 has been visualised in native chromatin, indicating opposite roles in structuring repressive or accessible chromatin domains. For example, at the mating-type loci in Schizosaccharomyces pombe, at pericentric heterochromatin and at the inactive X chromosome in mammals, striking differences between these distinct marks have been observed. H3 Lys9 methylation is also important to direct additional epigenetic signals such as DNA methylation--for example, in Neurospora crassa and in Arabidopsis thaliana. Together, the available data strongly establish histone lysine methylation as a central modification for the epigenetic organisation of eukaryotic genomes.

Animals↗
PubMed1993

Selective repression of transcriptional activators at a distance by the Drosophila Krüppel protein.

The Krüppel (Kr) protein, bound at kilobase distances from the start site of transcription, represses transcription by RNA polymerase II in mammalian cells. Repression is monotonically dependent on the dose of Kr protein and the presence of Kr binding site(s) on the DNA. These data suggest an inhibitory protein-protein interaction between the Kr protein and proximal transcription factors. Repression by Kr depends on the specific activator protein driving transcription. In particular, Kr protein selectively represses transcription mediated by the Sp1 glutamine-rich activation domain, tethered to the promoter by a GAL4 DNA-binding domain, but does not repress transcription stimulated by the acidic GAL4 activator. We believe this represents repression by a quenching interaction between DNA-bound Kr protein and the activation region of Sp1, rather than competition between Sp1 and Kr for a limiting transcriptional component. Selective, context-related repression affords an added layer of combinatorial control of gene expression by sequence-specific transcription factors.

Animals↗
PubMed2003

Elk-3 is a transcriptional repressor of nitric-oxide synthase 2.

The inducible isoform of nitric-oxide synthase (NOS2), a key enzyme catalyzing the dramatic increase in nitric oxide by lipopolysaccharide (LPS), plays an important role in the pathophysiology of endotoxemia and sepsis. Recent evidence suggests that Ets transcription factors may contribute to NOS2 induction by inflammatory stimuli. In this study, we investigated the role of Ets transcription factors in the regulation of NOS2 by LPS and transforming growth factor (TGF)-beta 1. Transient transfection assays in macrophages showed that Ets-2 produced an increase in NOS2 promoter activity, whereas the induction by Ets-1 was modest and NERF2 had no effect. Elk-3 (Net/Erp/Sap-2a) markedly repressed NOS2 promoter activity in a dose-dependent fashion, and overexpression of Elk-3 blunted the induction of endogenous NOS2 message. Mutation of the Net inhibitory domain of Elk-3, but not the C-terminal-binding protein interaction domain, partially alleviated this repressive effect. We also found that deletion of the Ets domain of Elk-3 completely abolished its repressive effect on the NOS2 promoter. LPS administration to macrophages led to a dose-dependent decrease in endogenous Elk-3 mRNA levels, and this decrease in Elk-3 preceded the induction of NOS2 mRNA. In a mouse model of endotoxemia, the expression of Elk-3 in kidney, lung, and heart was significantly down-regulated after systemic administration of LPS, and this down-regulation also preceded NOS2 induction. Moreover, TGF-beta 1 significantly increased endogenous Elk-3 mRNA levels that had been down-regulated by LPS in macrophages. This increase in Elk-3 correlated with a TGF-beta 1-induced down-regulation of NOS2. Taken together, our data suggest that Elk-3 is a strong repressor of NOS2 promoter activity and mRNA levels and that endogenous expression of Elk-3 inversely correlates with NOS2. Thus, Elk-3 may serve as an important mediator of NOS2 gene expression.

3T3 Cells↗
PubMed1999

DNA methylation in transcriptional repression of two differentially expressed X-linked genes, GPC3 and SYBL1.

Methylation of CpG islands is an established transcriptional repressive mechanism and is a feature of silencing in X chromosome inactivation. Housekeeping genes that are subject to X inactivation exhibit differential methylation of their CpG islands such that the inactive alleles are hypermethylated. In this report, we examine two contrasting X-linked genes with CpG islands for regulation by DNA methylation: SYBL1, a housekeeping gene in the Xq pseudoautosomal region, and GPC3, a tissue-specific gene in Xq26 that is implicated in the etiology of the Simpson-Golabi-Behmel overgrowth syndrome. We observed that in vitro methylation of either the SYBL1 or the GPC3 promoter resulted in repression of reporter constructs. In normal contexts, we found that both the Y and inactive X alleles of SYBL1 are repressed and hypermethylated, whereas the active X allele is expressed and unmethylated. Furthermore, the Y and inactive X alleles of SYBL1 were derepressed by treatment with the demethylating agent azadeoxycytidine. GPC3 is also subject to X inactivation, and the active X allele is unmethylated in nonexpressing leukocytes as well as in an expressing cell line, suggesting that methylation is not involved in the tissue-specific repression of this allele. The inactive X allele, however, is hypermethylated in leukocytes, presumably reflecting early X inactivation events that become important for gene dosage in expressing lineages. These and other data suggest that all CpG islands on Xq, including the pseudoautosomal region, are subject to X inactivation-induced methylation. Additionally, methylation of SYBL1 on Yq may derive from a process related to X inactivation that targets large chromatin domains for transcriptional repression.

Aza Compounds↗
PubMed1989

Delineation of three functional domains of the transcriptional activator encoded by the c-myb protooncogene.

The c-myb protooncogene encodes a sequence-specific DNA-binding protein (c-Myb) that induces transcriptional activation or repression. We have identified three functional domains of the mouse c-Myb protein that are responsible for DNA binding, transcriptional activation, and negative regulation, respectively. In addition to the DNA-binding domain, which is located near the N terminus, an adjacent region (the transcriptional activation domain) containing about 80 amino acids was found to be essential for transcriptional activation. Deletion of a region spanning about 175 amino acids of the C-proximal portion increased transcriptional activation markedly, revealing that this domain normally represses activation. Differences between the transcriptional activation and repression functions of c-Myb and v-Myb are discussed in the light of these functional domains. Our results suggest that transcriptional activation may be involved in transformation by myb gene products.

Actins↗
PubMed1995

Repression of activator-mediated transcription by herpes simplex virus ICP4 via a mechanism involving interactions with the basal transcription factors TATA-binding protein and TFIIB.

Infected-cell polypeptide 4 (ICP4) of herpes simplex virus is both a transcriptional activator and a repressor. It has been previously demonstrated that both SP1-activated transcription and USF-activated transcription are repressed by ICP4 without affecting basal transcription (B. Gu, R. Rivera-Gonzalez, C. A. Smith, and N. A. DeLuca, Proc. Natl. Acad. Sci. USA 90:9528-9532, 1993; R. Rivera-Gonzalez, A. N. Imbalzano, B. Gu, and N.A. DeLuca, Virology 202:550-564, 1994). In this study, it was found that ICP4 repressed the activation function of two other activators, VP16 and ICP4 itself, in vitro. ICP4 inhibited transcription by interfering with the formation of transcription initiation complexes without affecting transcription elongation. Repression of activator function required that an ICP4 DNA binding site was present in one orientation within approximately 45 bp 3' to the TATA box. DNA binding by ICP4 was necessary but not sufficient for repression. ICP4 has been shown to form tripartite complexes cooperatively with the TATA box-binding protein and TFIIB on DNA containing an ICP4 binding site and a TATA box (C. A. Smith, P. Bates, R. Rivera-Gonzalez, B. Gu, and N. DeLuca, J. Virol. 67:4676-4687, 1993). A region of ICP4 that enables the molecule to form tripartite complexes was also required in addition to the DNA binding domain for efficient repression. Moreover, repression was observed only when the ICP4 binding site was in a position that resulted in the formation of tripartite complexes. Together, the data suggest that ICP4 represses transcription by binding to DNA in a precise way so that it may interact with the basal transcription complex and inhibit some general step involved in the function of activators. The steps or interactions involved in transcriptional activation that are inhibited by ICP4 are discussed.

Base Sequence↗
PubMed1996

The ability of the inhibitory domain of the POU family transcription factor Oct-2 to interfere with promoter activation by different classes of activation domains is dependent upon the nature of the basal promoter elements.

The Oct-2 transcription factor contains an inhibitory domain which is able to repress transcription following DNA binding. Here we show that within the neuronally expressed Oct-2.5 form, the inhibitory domain can strongly inhibit activation by transcription factor activation domains which are either composed predominantly of acidic residues or contain the HOB motif, whereas it has a weaker effect or no effect on proline-rich activation domains and on a glutamine-rich domain. In contrast, the isolated inhibitory domain of Oct-2 can efficiently repress all types of activation domains. This effect is observed however, only on TATA box-containing promoters and not on promoters containing an initiator motif. This widespread inhibition of different activation domains and its dependence on the nature of the basal promoter elements indicate that the inhibitory domain is likely to act by contacting a common downstream target of activation domains within the basal transcriptional complex bound at the TATA box rather than quenching specific activation domains by direct interaction. These effects are discussed in terms of the functional role of the inhibitory domain within Oct-2.5 and the mechanism by which it acts.

Animals↗
PubMed2000

Positive and negative regulation of endogenous genes by designed transcription factors.

Gene regulation by imposed localization was studied by using designed zinc finger proteins that bind 18-bp DNA sequences in the 5' untranslated regions of the protooncogenes erbB-2 and erbB-3. Transcription factors were generated by fusion of the DNA-binding proteins to repression or activation domains. When introduced into cells these transcription factors acted as dominant repressors or activators of, respectively, endogenous erbB-2 or erbB-3 gene expression. Significantly, imposed regulation of the two genes was highly specific, despite the fact that the transcription factor binding sites targeted in erbB-2 and erbB-3 share 15 of 18 nucleotides. Regulation of erbB-2 gene expression was observed in cells derived from several species that conserve the DNA target sequence. Repression of erbB-2 in SKBR3 breast cancer cells inhibited cell-cycle progression by inducing a G(1) accumulation, suggesting the potential of designed transcription factors for cancer gene therapy. These results demonstrate the willful up- and down-regulation of endogenous genes, and provide an additional means to alter biological systems.

Amino Acid Sequence↗
PubMed2001

Repression of rRNA synthesis due to a secretory defect requires the C-terminal silencing domain of Rap1p in Saccharomyces cerevisiae.

A secretory defect causes specific transcriptional repression of both ribosomal protein and ribosomal RNA genes, suggesting the coupling of plasma membrane and ribosome syntheses. We previously reported that the rap1-17 allele, which produced C-terminally truncated Rap1p, derepressed transcription of ribosomal protein genes when the secretory pathway was blocked. In this paper, we demonstrate that the rap1-17 mutation also leads to significant attenuation of transcriptional repression of rRNA genes due to a secretory defect. In contrast, the rap1-2 temperature-sensitive allele containing a unique missense mutation in the middle of the coding sequence has only a weak effect on repression. These results suggest that the C-terminal silencing domain of Rap1p is required for transcriptional repression of rDNA in response to a secretory defect. We also demonstrated that transcriptional regulation of ribosomal protein genes in response to nitrogen limitation was not affected by the rap1-17 allele, suggesting that the mechanism of nitrogen response is distinct from that of the secretory response.

Alleles↗
PubMed2000

BSAP can repress enhancer activity by targeting PU.1 function.

PU.1 and BSAP are transcription factors crucial for proper B-cell development. Absence of PU.1 results in loss of B, T, and myeloid cells, while absence of BSAP results in an early block in B-cell differentiation. Both of these proteins bind to the immunoglobulin kappa chain 3' enhancer, which is developmentally regulated during B-cell differentiation. We find here that BSAP can repress 3' enhancer activity. This repression can occur in plasmacytoma lines or in a non-B-cell line in which the enhancer is activated by addition of the appropriate enhancer binding transcription factors. We show that the transcription factor PU.1 is a target of the BSAP-mediated repression. Although PU.1 and BSAP can physically interact through their respective DNA binding domains, this interaction does not affect DNA binding. When PU.1 function is assayed in isolation on a multimerized PU.1 binding site, BSAP targets a portion of the PU.1 transactivation domain (residues 7 to 30) for repression. The BSAP inhibitory domain (residues 358 to 385) is needed for this repression. Interestingly, the coactivator protein p300 can eliminate this BSAP-mediated repression. We also show that PU.1 can inhibit BSAP transactivation and that this repression requires PU.1 amino acids 7 to 30. Transfection of p300 resulted in only a partial reversal of PU.1-mediated repression of BSAP. When PU.1 function is assayed in the context of the immunoglobulin kappa chain 3' enhancer and associated binding proteins, BSAP represses PU.1 function by a distinct mechanism. This repression does not require the PU.1 transactivation or PEST domains and cannot be reversed by p300 expression. The possible roles of BSAP and PU.1 antagonistic activities in hematopoietic development are discussed.

B-Lymphocytes↗
PubMedDate not supplied

Proto-oncogene N-myc promoter is down regulated by the Wilms' tumor suppressor gene WT1.

The Wilms' tumor 1 (WT1) gene is a tumor suppressor gene that encodes a zinc-finger transcription factor. WT1 represses transcription of several growth factors and growth factor receptors. The N-myc proto-oncogene encodes a transcription factor which regulates cell growth and differentiation. N-myc is coexpressed with WT1 in the developing kidney and is overexpressed in many Wilms' tumors. Here, we show that the proto-oncogene N-myc promoter was down-regulated by WT1 in transient transfection assays. However, mutant WT1 (R394W) which has a mutation in the DNA binding domain could not repress the N-myc promoter. Electrophoretic mobility shift assays showed that the oligonucleotides containing the WT1 motifs could bind recombinant WT1 proteins. This suggests that the repression of the N-myc promoter is mediated through the WT1 binding sites. This finding may help to elucidate the relationship of WT1 and N-myc in tumorigenesis and renal development.

Binding Sites↗
PubMed2004

Groucho oligomerization is required for repression in vivo.

Drosophila Groucho (Gro) is a member of a family of metazoan corepressors with widespread roles in development. Previous studies indicated that a conserved domain in Gro, termed the Q domain, was required for repression in cultured cells and mediated homotetramerization. Evidence presented here suggests that the Q domain contains two coiled-coil motifs required for oligomerization and repression in vivo. Mutagenesis of the putative hydrophobic faces of these motifs, but not of the hydrophilic faces, prevents the formation of both tetramers and higher order oligomers. Mutagenesis of the hydrophobic faces of both coiled-coil motifs in the context of a Gal4-Gro fusion protein prevents repression of a Gal4-responsive reporter in S2 cells, while mutagenesis of a single motif weakens repression. The finding that the repression directed by the single mutants depends on endogenous wild-type Gro further supports the idea that oligomerization plays a role in repression. Overexpression in the fly of forms of Gro able to oligomerize, but not of a form of Gro unable to oligomerize, results in developmental defects and ectopic repression of Gro target genes in the wing disk. Although the function of several corepressors is suspected to involve oligomerization, these studies represent one of the first direct links between corepressor oligomerization and repression in vivo.

Amino Acid Motifs↗
PubMed2002

Y-box-binding protein YB-1 mediates transcriptional repression of human alpha 2(I) collagen gene expression by interferon-gamma.

We have demonstrated previously that a proximal element within the human alpha2(I) collagen gene (COL1A2) promoter mediates transcriptional repression by interferon-gamma (IFN-gamma), and designated this region the IFN-gamma response element (IgRE). Screening of a human fibroblast cDNA expression library with a radiolabeled IgRE probe exclusively yielded clones with a sequence identical to that of the transcription factor YB-1. Electrophoretic mobility shift assays (EMSA) using various IgRE-derived oligonucleotide probes containing serial two-base mutations showed that YB-1 protein was preferentially bound to the pyrimidine-rich sequence within the IgRE. This region is located immediately downstream of and partly overlaps the previously reported Sp1/Sp3 binding site. Overexpression of YB-1 in human dermal fibroblasts decreased steady state levels of COL1A2 mRNA and repressed COL1A2 promoter activity in a dose-dependent manner. This inhibitory effect of YB-1 on COL1A2 expression was abolished by mutations of the IgRE shown to prevent YB-1 binding in EMSA. In addition, these mutations also abolished the inhibitory effect of IFN-gamma, suggesting that YB-1 mediates the inhibitory action of IFN-gamma on COL1A2 promoter through its binding to the IgRE. Also, overexpression of a deletion mutant YB-1, which lacks the carboxyl-terminal domain, abrogated the repression of COL1A2 transcription by IFN-gamma. A functional correlation between IFN-gamma and YB-1 was further supported by luciferase assays using four tandem repeats of the Y-box consensus oligonucleotide linked to a minimal promoter. EMSA and Western blot analysis using cytoplasmic and nuclear proteins implied that IFN-gamma promotes the nuclear translocation of YB-1. Direct evidence for the nuclear translocation of YB-1 by IFN-gamma was further provided by using a YB-1-green fluorescent protein expression plasmid transfected into human fibroblasts. Altogether, this study represents the definitive identification of the transcription factor responsible for IFN-gamma-elicited inhibition of COL1A2 expression, namely YB-1.

CCAAT-Enhancer-Binding Proteins↗
PubMed1984

The immI region of Salmonella phage P22. 2. The influence of the cir mutations on the regulation of antirepressor synthesis.

The effects were studied of three clear plaque mutations of phage P22 (cir4-1, cir5-1 and cir6-1) on antirepressor synthesis. The mutant site cir4-1 has no influence on the expression of gene ant. The cir5-1 and cir6-1 mutations prevent the repression of early ant synthesis shortly after infection: P22 cir5-1 exhibits a strong ant-overproduction because it renders the cir5 repressor protein defective for turning off early ant expression (Harvey et al. 1981). P22 cir6-1 exhibits only a low level of constitutive ant synthesis insensitive to cir5-directed repression. Complementation experiments between P22 wild type or mutant in the cir5 or cir6 sites reveal the following phenotypes of the cir6-1 mutation: (1) The cir6-1 site behaves as a weak promotor site insensitive to cir5-directed repression of ant synthesis. (2) In the P22 cir5-1 cir6-1 double recombinant the cir6-1 site is cis dominant preventing ant overproduction as observed in simple P22 cir5-1 infections. (3) Some of the deficient phenotypes of P22 cir6-1 can be complemented by co-infecting P22 mutants carrying a cir6+ allele. These results are explained by the following model: The active cir5 repressor protein is a dimer (or oligomer) and the cir5-1 and cir6-1 mutations map in different domains influencing the repressing as well as the dimer forming activities of this protein. Which particular cir6-1 phenotype is observed depends on the experimental conditions employed, and on the promotor site (either pANT or cir6-1) from which ant expression procedes.(ABSTRACT TRUNCATED AT 250 WORDS)

Gene Expression Regulation↗
PubMed2001

Agonist-dependent repression mediated by mutant estrogen receptor alpha that lacks the activation function 2 core domain.

Nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) form heterogeneous complexes with various histone deacetylases (HDACs). In this report, we found that ER alpha-Delta AF2, a mutant estrogen receptor alpha (ER alpha) deleted for the C-terminal activation function 2 (AF2) core domain, directs estradiol (E(2))-dependent repression and impairs E(2)-induced transactivation by wild type ER alpha. This repression required coexpressed BRG1 in SW-13 cells that lack BRG1, the ATPase constituent of the chromatin-remodeling SWI.SNF complex, and was abolished by HDAC inhibitor trichostatin A. We further demonstrated that ER alpha-Delta AF2 constitutively associates with SMRT but binds DNA in an E(2)-dependent manner in vivo. These results suggest that ER alpha-Delta AF2 and similar mutant receptors recently found associated with certain tumors may actively perturb the normal E(2) signaling via SWI/SNF, N-CoR/SMRT, and HDAC.

Animals↗
PubMed2006

Cell fate determination factor DACH1 inhibits c-Jun-induced contact-independent growth.

The cell fate determination factor DACH1 plays a key role in cellular differentiation in metazoans. DACH1 is engaged in multiple context-dependent complexes that activate or repress transcription. DACH1 can be recruited to DNA via the Six1/Eya bipartite transcription (DNA binding/coactivator) complex. c-Jun is a critical component of the activator protein (AP)-1 transcription factor complex and can promote contact-independent growth. Herein, DACH1 inhibited c-Jun-induced DNA synthesis and cellular proliferation. Excision of c-Jun with Cre recombinase, in c-jun(f1/f1) 3T3 cells, abrogated DACH1-mediated inhibition of DNA synthesis. c-Jun expression rescued DACH1-mediated inhibition of cellular proliferation. DACH1 inhibited induction of c-Jun by physiological stimuli and repressed c-jun target genes (cyclin A, beta-PAK, and stathmin). DACH1 bound c-Jun and inhibited AP-1 transcriptional activity. c-jun and c-fos were transcriptionally repressed by DACH1, requiring the conserved N-terminal (dac and ski/sno [DS]) domain. c-fos transcriptional repression by DACH1 requires the SRF site of the c-fos promoter. DACH1 inhibited c-Jun transactivation through the delta domain of c-Jun. DACH1 coprecipitated the histone deacetylase proteins (HDAC1, HDAC2, and NCoR), providing a mechanism by which DACH1 represses c-Jun activity through the conserved delta domain. An oncogenic v-Jun deleted of the delta domain was resistant to DACH1 repression. Collectively, these studies demonstrate a novel mechanism by which DACH1 blocks c-Jun-mediated contact-independent growth through repressing the c-Jun delta domain.

Animals↗
PubMed2002

Suppression of promoter activity of the LAT gene by IE180 of pseudorabies virus.

The latency-associated transcript (LAT) gene is the only viral genomic region that is abundantly transcribed during pseudorabies virus (PrV) latent infection. The mechanism of reactivation of PrV from latency remains unknown. To analyze the regulation mechanism of the LAT promoter, we constructed a series of recombinant vectors in which various sequences upstream of LAT were linked to the chloramphenicol acetyltransferase (CAT) gene. Transcriptional efficiency was examined by cotransfection with plasmids carrying the PrV IE, EP0, or gD gene, respectively. Results showed that the activity of PrV LAT promoter was dramatically repressed by the IE180 protein and a TATA box and a putative IE180 binding site within the promoter were involved in this repression. To dissect the functional domains of IE180, we compared the relative repressive abilities of IE180 variants to the LAT promoter by transient transfection assays. Mutational analysis demonstrated that almost the whole IE180 (amino acid residues 1-1440) are essential for its repression to LAT promoter. To explore the possible mechanism of repression, an electrophoretic mobility shift assay (EMSA) using nuclear extracts from neuronal cells was performed and formation of protein-DNA complexes between IE180 and the oligonucleotide probe (-46 to -19, relative to the start site of LAT transcription) was demonstrated. The association of IE180 with the region encompassing the putative IE180 binding site and the TATA box upstream of PrV LAT gene was further confirmed by supershift of EMSA complexes using IE180 specific antibody. Thus, our results suggested that IE180 repressed the LAT promoter via an interaction between IE180, LAT promoter and cellular protein(s).

Animals↗
PubMed2000

The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression.

The orphan nuclear hormone receptor SHP interacts with a number of other nuclear hormone receptors and inhibits their transcriptional activity. Several mechanisms have been suggested to account for this inhibition. Here we show that SHP inhibits transactivation by the orphan receptor hepatocyte nuclear factor 4 (HNF-4) and the retinoid X receptor (RXR) by at least two mechanisms. SHP interacts with the same HNF-4 surface recognized by transcriptional coactivators and competes with them for binding in vivo. The minimal SHP sequences previously found to be required for interaction with other receptors are sufficient for interaction with HNF-4, although deletion results indicate that additional C-terminal sequences are necessary for full binding and coactivator competition. These additional sequences include those associated with direct transcriptional repressor activity of SHP. SHP also competes with coactivators for binding to ligand-activated RXR, and based on the ligand-dependent interaction with other nuclear receptors, it is likely that coactivator competition is a general feature of SHP-mediated repression. The minimal receptor interaction domain of SHP is sufficient for full interaction with RXR, as previously described. This domain is also sufficient for full coactivator competition. Functionally, however, full inhibition of RXR transactivation requires the presence of the C-terminal repressor domain, with only weak inhibition associated with this receptor interaction domain. Overall, these results suggest that SHP represses nuclear hormone receptor-mediated transactivation via two separate steps: first by competition with coactivators and then by direct effects of its transcriptional repressor function.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗