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PubMed2006

GenomeTrafac: a whole genome resource for the detection of transcription factor binding site clusters associated with conventional and microRNA encoding genes conserved between mouse and human gene orthologs.

Transcriptional cis-regulatory control regions frequently are found within non-coding DNA segments conserved across multi-species gene orthologs. Adopting a systematic gene-centric pipeline approach, we report here the development of a web-accessible database resource--GenomeTraFac (http://genometrafac.cchmc.org)--that allows genome-wide detection and characterization of compositionally similar cis-clusters that occur in gene orthologs between any two genomes for both microRNA genes as well as conventional RNA-encoding genes. Each ortholog gene pair can be scanned to visualize overall conserved sequence regions, and within these, the relative density of conserved cis-element motif clusters form graph peak structures. The results of these analyses can be mined en masse to identify most frequently represented cis-motifs in a list of genes. The system also provides a method for rapid evaluation and visualization of gene model-consistency between orthologs, and facilitates consideration of the potential impact of sequence variation in conserved non-coding regions to impact complex cis-element structures. Using the mouse and human genomes via the NCBI Reference Sequence database and the Sanger Institute miRBase, the system demonstrated the ability to identify validated transcription factor targets within promoter and distal genomic regulatory regions of both conventional and microRNA genes.

Animals↗

PubMed2005

AthaMap web tools for database-assisted identification of combinatorial cis-regulatory elements and the display of highly conserved transcription factor binding sites in Arabidopsis thaliana.

The AthaMap database generates a map of cis-regulatory elements for the Arabidopsis thaliana genome. AthaMap contains more than 7.4 x 10(6) putative binding sites for 36 transcription factors (TFs) from 16 different TF families. A newly implemented functionality allows the display of subsets of higher conserved transcription factor binding sites (TFBSs). Furthermore, a web tool was developed that permits a user-defined search for co-localizing cis-regulatory elements. The user can specify individually the level of conservation for each TFBS and a spacer range between them. This web tool was employed for the identification of co-localizing sites of known interacting TFs and TFs containing two DNA-binding domains. More than 1.8 x 10(5) combinatorial elements were annotated in the AthaMap database. These elements can also be used to identify more complex co-localizing elements consisting of up to four TFBSs. The AthaMap database and the connected web tools are a valuable resource for the analysis and the prediction of gene expression regulation at http://www.athamap.de.

Arabidopsis↗

PubMed2006

ExtraTrain: a database of Extragenic regions and Transcriptional information in prokaryotic organisms.

BACKGROUND: Transcriptional regulation processes are the principal mechanisms of adaptation in prokaryotes. In these processes, the regulatory proteins and the regulatory DNA signals located in extragenic regions are the key elements involved. As all extragenic spaces are putative regulatory regions, ExtraTrain covers all extragenic regions of available genomes and regulatory proteins from bacteria and archaea included in the UniProt database. DESCRIPTION: ExtraTrain provides integrated and easily manageable information for 679816 extragenic regions and for the genes delimiting each of them. In addition ExtraTrain supplies a tool to explore extragenic regions, named Palinsight, oriented to detect and search palindromic patterns. This interactive visual tool is totally integrated in the database, allowing the search for regulatory signals in user defined sets of extragenic regions. The 26046 regulatory proteins included in ExtraTrain belong to the families AraC/XylS, ArsR, AsnC, Cold shock domain, CRP-FNR, DeoR, GntR, IclR, LacI, LuxR, LysR, MarR, MerR, NtrC/Fis, OmpR and TetR. The database follows the InterPro criteria to define these families. The information about regulators includes manually curated sets of references specifically associated to regulator entries. In order to achieve a sustainable and maintainable knowledge database ExtraTrain is a platform open to the contribution of knowledge by the scientific community providing a system for the incorporation of textual knowledge. CONCLUSION: ExtraTrain is a new database for exploring Extragenic regions and Transcriptional information in bacteria and archaea. ExtraTrain database is available at http://www.era7.com/ExtraTrain/.

Archaea↗

PubMed2006

Zebrafish arylalkylamine-N-acetyltransferase genes - targets for regulation of the circadian clock.

Daily rhythms of melatonin production are controlled by changes in the activity of arylalkylamine-N-acetyltransferase (AANAT). Zebrafish possess two aanats, aanat1 and aanat2; the former is expressed only in the retina and the latter is expressed in both the retina and the pineal gland. Here, their differential expression and regulation were studied using transcript quantification and transient and stable in vivo and in vitro transfection assays. In the pineal gland, the aanat2 promoter exhibited circadian clock-controlled activity, as indicated by circadian rhythms of Enhanced green fluorescent protein (EGFP) mRNA in AANAT2:EGFP transgenic fish. In vivo transient expression analyses of the aanat2 promoter indicated that E-box and photoreceptor conserved elements (PCE) are required for expression in the pineal gland. In the retina, the expression of both genes was characterized by a robust circadian rhythm of their transcript levels. In constant darkness, the rhythmic expression of retinal aanat2 persisted while the aanat1 rhythm disappeared; indicating that the former is controlled by a circadian clock and the latter is also light driven. In the light-entrainable clock-containing PAC-2 zebrafish cell line, both stably transfected aanat1 and aanat2 promoters exhibited a clock-controlled circadian rhythm, characteristic for an E-box-driven expression. Transient co-transfection experiments in NIH-3T3 cells revealed that the two, E-box- and PCE-containing, promoters are driven by the synergistic action of BMAL/CLOCK and orthehodenticle homeobox 5. This study has revealed a shared mechanism for the regulation of two related genes, yet describes their differential phases and photic responses which may be driven by other gene-specific regulatory mechanisms and tissue-specific transcription factor profiles.

Animals↗

PubMed2006

trans meets cis in MADS science.

The interaction between a transcription factor and its binding site at the DNA is an integral part of transcriptional regulatory networks, which is fundamental for an understanding of biological processes. An example is the family of MADS domain transcription factors, which represent key regulators of processes in yeast, animals and plants. However, despite our extensive knowledge of these transcription factors, limited information is available on the cis-elements to which these proteins bind or how these elements are defined. Here, we discuss the current understanding of MADS protein binding sites and compare data from various organisms. This information can help us in developing algorithms to predict binding sites for MADS domain transcription factors, which would be a significant step forward in the identification of "down-stream" target genes and the elucidation of transcriptional networks.

Base Sequence↗

PubMed1996

Identification of elements in the PDA1 promoter of Nectria haematococca necessary for a high level of transcription in vitro.

Expression of the PDA1 gene in the ascomycete Nectria haematococca MPVI (anamorph: Fusarium solani) is induced by exposure of mycelium to pisatin, an isoflavonoid phytoalexin produced by its host plant, garden pea. The PDA1 gene encodes a cytochrome P-450 monooxygenase which detoxifies pisatin. Regulatory elements controlling transcription from the PDA1 promoter were identified using a homologous Nectria in vitro transcription system through analysis of 5' deletions, specific oligonucleotide competition, and fusion of upstream segments to a heterologous promoter. A promoter-distal element which provided transcriptional activation was localized to a 35-bp region positioned -514 to -483 upstream of the transcriptional start site. This 35-bp region binds a previously characterized pisatin-responsive DNA-binding factor (PRF) and thus may provide pisatin-responsive control of transcription. A second promoter-proximal positive-acting region was found to be necessary for promoter transcription in both homologous and heterologous extracts, and so is likely to bind less genespecific transcription activator(s). A negative-acting element located between these two positive regions may act to make the positive-acting elements interdependent. The identification of an activator responding to pisatin provides a model for the control of a number of genes and processes controlled by host-specific signals, particularly the flavonoids.

Base Sequence↗

PubMed2026

Small Copy Number Neutral Intrachromosomal Translocation of PAX6 and Aniridia.

IMPORTANCE: Approximately 5% to 10% of individuals with classic aniridia do not receive a molecular diagnosis after clinical testing for variants in PAX6 and its downstream regulatory region. OBJECTIVE: To apply optical genome mapping (OGM) and long-read whole-genome sequencing (lrWGS) to diagnose an individual with unexplained classic aniridia. DESIGN, SETTING, AND PARTICIPANTS: High-quality DNA was extracted from the blood of a 16-year-old male patient with classic aniridia and prior negative clinical test results that included sequencing and copy number analysis of PAX6 exons and downstream regulatory region as well as genomic analysis via short-read whole-genome sequencing (srWGS) and analyzed using OGM and lrWGS. All analyses were performed in a research laboratory in Wisconsin from January 2019 to September 2025. INTERVENTIONS: OGM and lrWGS. MAIN OUTCOMES AND MEASURES: Identification of a structural variant disrupting PAX6 expression in an individual with classic aniridia, following negative prior testing including srWGS. RESULTS: OGM identified a 55-kb deletion on 11p13 encompassing all PAX6 exons and exon 12 of ELP4, with insertion of this segment into 11q21. lrWGS delineated the exact breakpoints, confirming that the downstream regulatory region, required for normal PAX6 expression, remained at the 11p13 locus. Consequently, the translocated copy of PAX6 at 11q21 is expected to lack expression due to the loss of its essential regulatory elements. CONCLUSIONS AND RELEVANCE: These findings in an individual with classic aniridia harboring an intrachromosomal rearrangement at the PAX6 locus identified by OGM and lrWGS may represent the smallest reported structural variant to separate the PAX6 coding sequence from its downstream regulatory region. This structural variant may have fallen below the detection threshold of srWGS due to its balanced nature and small size, suggesting OGM and lrWGS would be needed for definitive identification.

Aniridia↗

PubMed2005

Comparative studies of transcriptional regulation mechanisms in a group of eight gamma-proteobacterial genomes.

Experimental data on the Escherichia coli transcriptional regulation has enabled the construction of statistical models to predict new regulatory elements within its genome. Far less is known about the transcriptional regulatory elements in other gamma-proteobacteria with sequenced genomes, so it is of great interest to conduct comparative genomic studies oriented to extracting biologically relevant information about transcriptional regulation in these less studied organisms using the knowledge from E. coli. In this work, we use the information stored in the TRACTOR_DB database to conduct a comparative study on the mechanisms of transcriptional regulation in eight gamma-proteobacteria and 38 regulons. We assess the conservation of transcription factors binding specificity across all the eight genomes and show a correlation between the conservation of a regulatory site and the structure of the transcription unit it regulates. We also find a marked conservation of site-promoter distances across the eight organisms and a correspondence of the statistical significance of co-occurrence of pairs of transcription factor binding sites in the regulatory regions, which is probably related to a conserved architecture of higher-order regulatory complexes in the organisms studied. The results obtained in this study using the information on transcriptional regulation in E. coli enable us to conclude that not only transcription factor-binding sites are conserved across related species but also several of the transcriptional regulatory mechanisms previously identified in E. coli.

Binding Sites↗

PubMed1998

Functional analysis of the proximal CCR5 promoter.

Two promoters for the CCR5 gene, termed Pu and Pd, corresponding to the upstream and downstream initiation sites, respectively, have been described. We show here that the proximal promoter, Pd, is used two- to fivefold more frequently than Pu in primary activated T cells and in the transformed T cell line PM1. Because of its importance in CCR5 transcription we characterized the transcriptional activity of this promoter. Pd contains a pair of consensus TATA elements (nt -19 and -31) and several potential regulatory elements and transcription factor-binding sites, including those for STAT, NF-kappaB, AP-1, NF-AT, and CD28RE. Using a transfected reporter vector, we found the promoter to be highly active and cell type specific. By 5' deletion analysis, the minimal CCR5 promoter was localized to a 225-nucleotide region (nt -189 to +36). This region contained the two TATA elements, a CD28RE consensus sequence, an AP-1-binding site, and two STAT-binding sites. The 1.9-kb intron appeared to have a negative influence on reporter gene activity, suggesting the presence of a negative element in this region. In addition, an upstream negative element was detected in the region nt -988 to -588. Mutagenesis of the TATA elements, of the NF-kappaB-, and AP-1-, and STAT-binding sites, and of the CD28RE indicated the importance of each of these in transcription. Finally, the NF-kappaB/Rel family member, p65(RelA), was a potent activator of the CCR5 promoter.

Base Sequence↗

PubMed2026

ChromBERT-tools: a versatile toolkit for context-specific regulatory representations of transcription regulators across different cell types.

SUMMARY: Representations that encode the genome-wide regulatory behavior of transcription regulators provide a foundation for flexible transcription modeling and in silico regulatory analysis. Existing regulator representations are commonly derived from gene co-expression, motif annotations, or static protein features, which capture useful but limited aspects of regulator identity but do not directly model how regulators participate in region-specific regulatory programs across the genome. ChromBERT addresses this gap by learning context-aware regulatory representations from large-scale ChIP-seq data. However, routine bioinformatics applications require lightweight, accessible, and modular tools for generating, adapting, and interpreting these representations in user-defined biological contexts. Here, we present ChromBERT-tools, a user-oriented toolkit built upon ChromBERT that converts its regulatory representation framework into practical workflows for customizable analysis across cellular contexts. ChromBERT-tools provides command-line interfaces and Python APIs organized into three functional layers: representation generation, predictive modeling, and regulatory interpretation. The representation generation layer produces representations of genomic regions and transcription regulators. The predictive modeling layer fine-tunes ChromBERT for genome-wide regulatory activity prediction through classification or regression tasks, with optimized implementation to reduce running time and computational resource requirements. The regulatory interpretation layer supports inference of the context-specific roles of cis-regulatory elements and transcription regulators. These modules can be used independently or integrated into end-to-end workflows, enabling flexible analyses across diverse datasets. ChromBERT-tools lowers the barrier to applying context-specific regulatory representations in routine genomic analyses. AVAILABILITY AND IMPLEMENTATION: ChromBERT-tools is freely available at https://github.com/TongjiZhanglab/ChromBERT-tools, with documentation at https://chrombert-tools.readthedocs.io/en/latest/. A frozen archival snapshot is available on Zenodo under DOI: 10.5281/zenodo.20094206.

Software↗

PubMed2006

The yeast CPC2/ASC1 gene is regulated by the transcription factors Fhl1p and Ifh1p.

CPC2/ASC1 is one of the most abundantly transcribed genes in Saccharomyces cerevisiae. It encodes a ribosome-associated Gbeta-like WD protein, which is highly conserved from yeast to man. Here, we show that CPC2 transcription depends on the carbon source and is induced during utilization of the sugar glucose. CPC2 promoter deletion and insertion analyses identified two upstream activation sequence elements for CPC2, which are required for basal expression and regulation. One of these upstream activation sequence elements has an ATGTACGGATGT motif, which has previously been described as a putative binding site for the forkhead-like transcription factor Fhl1p. Deletion of FHL1 reduces CPC2 transcription significantly in presence of glucose, but has no effect when the non-fermentable carbon source ethanol is provided. Increased amounts of the Fhl1p co-regulator Ifh1p induce CPC2 transcription even when ethanol is utilized. These data suggest that the interaction between Fhl1p and Ifh1p is critical for the regulation of CPC2 transcription during utilization of different carbon sources.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Interleukin-1beta attenuates renin gene expression via a mitogen-activated protein kinase kinase-extracellular signal-regulated kinase and signal transducer and activator of transcription 3-dependent mechanism in As4.1 cells.

The precise mechanism by which cytokines such as IL-1beta negatively modulate expression of the renin gene remains incomplete. IL-1beta can repress renin transcription under both baseline and retinoic acid-stimulated conditions in As4.1 cells, a renin-expressing cell line derived from the kidney. This repression does not require a negative regulatory element present in the renin enhancer but is optimal in the presence of the entire renin enhancer. Three tandem copies of the retinoic acid response element is sufficient to attenuate the retinoic acid-response by IL-1beta. The decrease in retinoic acid-induced renin promoter activity in response to IL-1beta was blocked with the general tyrosine kinase inhibitor Genistein. IL-1beta caused an increase in the phosphorylation of ERK, but not p38MAPK or c-Jun N-terminal kinase. PD98059, an Erk kinase inhibitor, significantly decreased IL-1beta-mediated phosphorylation of ERK1/2, and attenuated the repression of baseline renin transcription in response to IL-1beta. PD98059 partially reversed the IL-1beta effect on retinoic acid-mediated transcription. To further investigate this mechanism, we searched the downstream effectors of ERK1/2 pathway. Although there was no effect of IL-1beta on the phosphorylation of ELK, Janus kinase 2, or signal transducers and activators of transcription (STAT) 1, IL-1beta significantly increased tyrosine-phosphorylation of STAT3, an effect attenuated by PD98059. STAT3 overexpression significantly repressed transcription of the renin gene, whereas small interfering RNA-mediated knockdown of STAT3 increased renin at baseline and attenuated the IL-1beta response. We conclude that in As4.1 cells, IL-1beta down-regulates renin gene expression via a mechanism involving the Erk-STAT3 pathway.

Animals↗

PubMed2002

Functional equivalency of amphioxus and vertebrate Pax258 transcription factors suggests that the activation of mid-hindbrain specific genes in vertebrates occurs via the recruitment of Pax regulatory elements.

Pax genes encode transcription factors that control key developmental decisions in various animal phyla. The Pax2/5/8 subfamily plays a key role in specification and/or maintenance of vertebrate mid-hindbrain boundary (MHB) region by directly regulating expression of other genes, most notably En2. In the invertebrate chordate amphioxus, expression of AmphiPax2/5/8 is found in many sites that are homologous to the regions of the vertebrate embryo expressing orthologous genes Pax2, Pax5 or Pax8. However, no co-expression of AmphiPax2/5/8 and AmphiEn is detected in the region of the neural tube that might correspond to the vertebrate MHB. Based on this observation and the absence of AmphiWnt expression in this region it appears that amphioxus does not have a MHB. Here we investigated the possibility that the AmphiPax2/5/8, as a key component of MHB development, has lost some of the properties of its vertebrate counterparts. We have analyzed both the DNA-binding and transactivation properties of AmphiPax2/5/8 as well as its ability to interact with the groucho co-repressor. In all these assays AmphiPax2/5/8 is indistinguishable from the human Pax5. In addition, we found two alternatively spliced AmphiPax2/5/8 isoforms that function similarly to the alternatively spliced isoforms of human Pax8. Analysis of the AmphiEn regulatory region provided no evidence for AmphiPax2/5/8 binding and transactivation. Therefore, in amphioxus, AmphiPax2/5/8, although capable of performing all the necessary functions has not been recruited for a developmental mechanism which usually sets up MHB development in vertebrates.

3T3 Cells↗

PubMed1999

BTEB2, a Krüppel-like transcription factor, regulates expression of the SMemb/Nonmuscle myosin heavy chain B (SMemb/NMHC-B) gene.

We have recently characterized the promoter region of the rabbit embryonic smooth muscle myosin heavy chain (SMemb/NMHC-B) gene and identified the 15-bp sequence, designated SE1, located at -105 from the transcriptional start site as an important regulatory element for its transcriptional activity in a smooth muscle cell (SMC) line. In this study, we attempted to isolate cDNA clones encoding for the transcription factors that control the expression of the SMemb gene through binding to this cis-regulatory element. We screened a lambdagt11 cDNA library prepared from C2/2 cells, a rabbit-derived SMC line, by using a radiolabeled concatenated oligonucleotide containing SE1 as a probe. Sequence analysis revealed that one of the cDNA clones corresponds to the rabbit homologue of basic transcriptional element binding protein-2 (BTEB2), which has previously been identified as one of the Krüppel-like transcription factor. Gel mobility shift assays and antibody supershift analyses with nuclear extracts from C2/2 cells indicate that BTEB2 is a major component of nuclear factor:SE1 complexes. Furthermore, a glutathione S-transferase-BTEB2 fusion protein binds to the SE1 in a sequence-specific manner. In support of the functionality of BTEB2 binding, basal promoter activity and BTEB2-induced transcriptional activation were markedly attenuated by the disruption of the SE1. In adult rabbit tissues, BTEB2 mRNA was most highly expressed in intestine, urinary bladder, and uterus. BTEB2 mRNA levels were downregulated in rabbit aorta during normal development. Moreover, immunohistochemical analysis indicated a marked induction of BTEB2 protein in the neointimal SMC after balloon injury in rat aorta. These results suggest that BTEB2 mediates the transcriptional regulation of the SMemb/NMHC-B gene and possibly plays a role in regulating gene expression during phenotypic modulation of vascular SMC.

Age Factors↗

PubMed1991

Three individual regulatory elements of the promoter positively activate the transcription of the murine gene encoding granulocyte colony-stimulating factor.

At least three regulatory elements GPE1, GPE2 and GPE3 (G-CSF promoter elements) controlling the gene (G-CSF) encoding granulocyte colony-stimulating factor (G-CSF) are indispensable for the constitutive expression of the G-CSF gene in human CHU-2 cells and for its lipopolysaccharide(LPS)-inducible expression in macrophages. The enhancer activities of each regulatory element were examined with or without the SV40 enhancer element placed downstream from the reporter gene. A GPE1 tetramer mediated the constitutive expression in CHU-2 cells, and the LPS-inducible expression in macrophage cell lines, while the GPE2 element was active in CHU-2 and LPS-treated macrophage cell lines only in combination with the SV40 enhancer. A GPE3 tetramer had efficient enhancer activity in CHU-2 cells but not in macrophage cell lines without the SV40 enhancer. In combination with the SV40 enhancer, GPE3 worked as an LPS-inducible enhancer element in macrophage BAM3 cells. Gel retardation assay indicated that the CHU-2 and the macrophage cells contained nuclear factors which specifically bound to each GPE sequence.

Animals↗

PubMed1987

Structural organization of the mouse mitochondrial aspartate aminotransferase gene.

Structural organization of the entire mouse mitochondrial aspartate aminotransferase (EC 2.6.1.1) gene was determined by analyzing the overlapping genomic clones obtained from a Charon 4A DNA library. The gene is 25 X 10(3) base-pairs long and contains ten exons interrupted by nine introns of various sizes. The 5' and 3'-flanking regions, the exact sizes and boundaries of the exon blocks including the transcription-initiation sites were determined. The 5' end of the gene lacks the prototypical 5' transcriptional regulatory sequence elements, such as TATA and CAAT boxes, but contains G + C-rich sequences, two putative binding sites for a cellular transcription factor, Sp1, and multiple transcription-initiation sites. Moreover, the sequences around the transcription-initiation sites are compatible with the formation of a number of potentially stable stem-loop structures. The leader sequence, which is essential for the transport of the protein into the mitochondria, is coded by the first exon and is separated from the mature protein by the first intron. The pyridoxal 5'-phosphate-binding domain, consisting of seven alternating beta-sheets and alpha-helical polypeptide strands, is separated by four introns present at the ends of alpha-helices. These genomic DNA structures suggest that the introns were not inserted into a previously uninterrupted coding sequence, but rather are products of evolution of the ancestral gene. However, a further correlation between the positions of introns relative to the well-defined structural domains of the mature protein was not obvious.

Animals↗

PubMed2006

A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter.

We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.

Binding Sites↗

PubMed1998

Differential transcriptional regulation of the human squalene synthase gene by sterol regulatory element-binding proteins (SREBP) 1a and 2 and involvement of 5' DNA sequence elements in the regulation.

Transcription of the human squalene synthase (HSS) gene is regulated by variations in the level of cellular cholesterol. Three regulatory elements in the HSS promoter region are known to be involved in the regulation: 1) a modified sterol regulatory element (SRE) 1 (HSS-SRE-1), 2) an inverted SRE-3 (Inv-SRE-3), 3) an inverted Y box (Inv-Y-Box). We report here the regulatory role of distinct cis-elements in the HSS promoter by using mutants of an HSS-luciferase promoter reporter. The activity of a wild-type promoter reporter transiently transfected into HepG-2 cells is increased by sterol depletion of the cells or by coexpression of mature forms of the SRE-binding proteins (SREBP) 1a and SREBP-2. Differential activation by SREBP-1a and SREBP-2 of the reporter gene mutated at various regions of the promoter is observed. Mutation of either the HSS-SRE-1 or the Inv-SRE-3 sequence diminished the activation by SREBP-1a and by sterol depletion but did not affect the activation by SREBP-2. Simultaneous mutations of both of these sequences almost completely abolished activation of the promoter by SREBP-1a or by sterol depletion, but activation by SREBP-2 was retained at 70%. Mutation of the Inv-Y-Box sequence element decreased the activity of the promoter by 50% or more, and if mutated together with both SREs, the activation was almost completely abolished. Mutation of any single GC box of the two located at -40 to -57 did not affect activity, whereas simultaneous mutation of the two decreased activation by SREBP-2 by 60%, by lipid depletion by 20%, and had no effect on the activation by SREBP-1a. A Y box motif at -159 to -166 and an SRE-like sequence element (SRE-1(8/10)) at position -101 to -108 are also involved in the sterol regulation. These results indicate that the complex sterol-mediated transcriptional regulation of the HSS gene is due to the presence of multiple copies of diverse cis elements in the HSS promoter. The differential activation of the HSS promoter may point to specific role of the SREBPs in cholesterogenesis.

CCAAT-Enhancer-Binding Proteins↗