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Results for “regulatory element transcripts”

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PubMed2006

Molecular cloning and characterization of the mouse Na+ sulfate cotransporter gene (Slc13a4): Structure and expression.

Sulfate is an essential ion required for numerous functions in mammalian physiology. Due to its hydrophilic nature, cells require sulfate transporters on their plasma membranes to allow entry of sulfate into cells. In this study, we identified a new mouse Na(+)-sulfate cotransporter (mNaS2), characterized its tissue distribution and determined its cDNA and gene (Slc13a4) structures. mNaS2 mRNA was expressed in placenta, brain, lung, eye, heart, testis, thymus and liver. The mouse NaS2 cDNA spans 3384 nucleotides and its open frame encodes a protein of 624 amino acids. Slc13a4 maps to mouse chromosome 6B1 and contains 16 exons, spanning over 40 kb in length. Its 5'-flanking region contains CAAT- and GC-box motifs and a number of putative transcription factor binding sites, including GATA-1, MTF-1, STAT6 and HNF4 consensus sequences. This is the first study to define the tissue distribution of mNaS2 and resolve its cDNA and gene structures, which will allow us to investigate mNaS2 gene expression in vivo and determine its role in mammalian physiology.

5' Flanking Region↗

PubMed2006

Histone deacetylase inhibitors: a novel therapeutic approach to Huntington's disease (complex mechanism of neuronal death).

Huntington's disease is an autosomal dominantly inherited neurodegenerative disorder caused by a polyglutamine repeat expansion. The onset of HD leads to problems with movement, cognition, and behavioral functioning and there is currently no effective treatment. The mechanism by which mutant huntingtin causes neuronal dysfunction is not known. However, multiple pathologic mechanisms have been discovered. Recent studies provide strong evidence for transcriptional dysregulation as a mechanism of HD pathogenesis. The control of eukaryotic gene expression depends on the modification of histone proteins associated with specific genes; acetylation and deacetylation of histones play a critical role in gene expression. Studies in numerous HD models have shown that mutant huntingtin expression leads to a change in histone acetyl transferase (HAT) activity and suggest that aberrant HAT activity may be an underlying mechanism of transcriptional dysregulation in HD. Furthermore, recent studies have shown a therapeutic role for histone deacetylase (HDAC) inhibitors in a number of HD models. In this review we discuss a number of studies that use HDAC inhibitors as therapeutic agents in HD models. These studies demonstrate that HDAC inhibitors are a promising therapeutic approach for the treatment of HD.

Acetylation↗

PubMed1994

Protein-DNA interactions in the promoter region of the amyloid precursor protein (APP) gene in human neocortex.

We have investigated protein-DNA interactions in the proximal promoter of the human amyloid precursor protein (APP) gene in temporal lobe neocortical nuclei isolated from control and Alzheimer disease (AD) affected brains. We report that the human APP 5' promoter sequence from -203 to +55 bp, which has been previously reported to contain essential regulatory elements for APP gene transcription, lies in a deoxyribonuclease I, micrococcal nuclease- and restriction endonuclease-sensitive, G+C-rich nucleosome-free gap flanked both 5' and 3' by typical nucleosome structures. As analyzed by electrophoretic mobility shift assay, this extended internucleosomal linker DNA is heavily occupied by nuclear protein factors, and interacts differentially with nuclear protein extracts obtained from HeLa and human brain neocortical nuclei. This suggests that the chromatin conformation of the APP gene promoter may vary in different cell types, and may correlate with differences in APP gene expression. Human recombinant transcription factors AP1, SP1 and TFIID (but not AP2 or brain histones H1, H2B and H4) interact with the -203 to +55 bp of the human APP promoter sequence. Only minor differences were observed in the chromatin structure of the immediate APP promoter between non-AD and AD affected neocortical nuclei, suggesting either that post-transcriptional processes, or that regulatory elements lying elsewhere in the APP gene may be important in the aberrant accumulation of the APP gene product.

Aged↗

PubMed2006

Nrf2 gene deletion fails to alter psychostimulant-induced behavior or neurotoxicity.

The transcription factor NF-E2-related factor (Nrf2) regulates the induction of phase 2 detoxifying enzymes by oxidative stress, including synthesis of the catalytic subunit (xCT) of the heterodimeric cystine-glutamate exchanger (system xc-). Repeated cocaine treatment in rats causes persistent neuroadaptations in glutamate neurotransmission in the nucleus accumbens that result, in part, from reduced activity of system xc-. Since in vitro under- or over-expression of Nrf2 regulates system xc- activity and xCT content, it was hypothesized that in vivo deletion of the Nrf2 gene would: 1) decrease system xc- activity, 2) produce a behavioral phenotype resembling that elicited by chronic cocaine administration, and 3) enhance dopamine depletion after methamphetamine-induced oxidative stress. In all three experiments no genotypic difference was measured between mice sustaining homozygous Nrf2 gene deletion and wild-type littermates. Thus, while Nrf2 is a transcriptional regulator of xCT and capable of protecting cells from oxidative stress, following Nrf2 gene deletion this role can be partially compensated by other mechanisms and methamphetamine-induced oxidative stress and dopamine toxicity does not significantly involve Nrf2.

Amino Acid Transport System y+↗

PubMed2006

RegTransBase--a database of regulatory sequences and interactions in a wide range of prokaryotic genomes.

RegTransBase is a manually curated database of regulatory interactions in prokaryotes that captures the knowledge in public scientific literature using a controlled vocabulary. Although several databases describing interactions between regulatory proteins and their binding sites are already being maintained, they either focus mostly on the model organisms Escherichia coli and Bacillus subtilis or are entirely computationally derived. RegTransBase describes a large number of regulatory interactions reported in many organisms and contains the following types of experimental data: the activation or repression of transcription by an identified direct regulator, determining the transcriptional regulatory function of a protein (or RNA) directly binding to DNA (RNA), mapping or prediction of a binding site for a regulatory protein and characterization of regulatory mutations. Currently, RegTransBase content is derived from about 3000 relevant articles describing over 7000 experiments in relation to 128 microbes. It contains data on the regulation of about 7500 genes and evidence for 6500 interactions with 650 regulators. RegTransBase also contains manually created position weight matrices (PWM) that can be used to identify candidate regulatory sites in over 60 species. RegTransBase is available at http://regtransbase.lbl.gov.

Bacterial Proteins↗

PubMed2005

Single-nucleosome mapping of histone modifications in S. cerevisiae.

Covalent modification of histone proteins plays a role in virtually every process on eukaryotic DNA, from transcription to DNA repair. Many different residues can be covalently modified, and it has been suggested that these modifications occur in a great number of independent, meaningful combinations. Published low-resolution microarray studies on the combinatorial complexity of histone modification patterns suffer from confounding effects caused by the averaging of modification levels over multiple nucleosomes. To overcome this problem, we used a high-resolution tiled microarray with single-nucleosome resolution to investigate the occurrence of combinations of 12 histone modifications on thousands of nucleosomes in actively growing S. cerevisiae. We found that histone modifications do not occur independently; there are roughly two groups of co-occurring modifications. One group of lysine acetylations shows a sharply defined domain of two hypo-acetylated nucleosomes, adjacent to the transcriptional start site, whose occurrence does not correlate with transcription levels. The other group consists of modifications occurring in gradients through the coding regions of genes in a pattern associated with transcription. We found no evidence for a deterministic code of many discrete states, but instead we saw blended, continuous patterns that distinguish nucleosomes at one location (e.g., promoter nucleosomes) from those at another location (e.g., over the 3' ends of coding regions). These results are consistent with the idea of a simple, redundant histone code, in which multiple modifications share the same role.

Chromatin Immunoprecipitation↗

PubMed2007

The SCL transcriptional network and BMP signaling pathway interact to regulate RUNX1 activity.

Hematopoietic stem cell (HSC) development is regulated by several signaling pathways and a number of key transcription factors, which include Scl/Tal1, Runx1, and members of the Smad family. However, it remains unclear how these various determinants interact. Using a genome-wide computational screen based on the well characterized Scl +19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice. Smad6, Bmp4, and Runx1 transcripts are concentrated along the ventral aspect of the E10.5 dorsal aorta in the aorta-gonad-mesonephros region from which HSCs originate. Moreover, Smad6, an inhibitor of Bmp4 signaling, binds and inhibits Runx1 activity, whereas Smad1, a positive mediator of Bmp4 signaling, transactivates the Runx1 promoter. Taken together, our results integrate three key determinants of HSC development; the Scl transcriptional network, Runx1 activity, and the Bmp4/Smad signaling pathway.

Animals↗

PubMed2006

Methylation of the human papillomavirus-18 L1 gene: a biomarker of neoplastic progression?

Epigenetic transcriptional regulation plays an important role in the life cycle of human papillomaviruses (HPVs) and the carcinogenic progression of anogenital HPV associated lesions. We performed a study designed to assess the methylation status of the HPV-18 genome, specifically of the late L1 gene, the adjacent long control region (LCR), and part of the E6 oncogene in cervical specimens with a range of pathological diagnoses. In asymptomatic infections and infections with precancerous (precursor) lesions, HPV-18 DNA was mostly unmethylated, with the exception of four samples where hypermethylation of L1 was detected. In contrast, L1 sequences were strongly methylated in all cervical carcinomas, while the LCR and E6 remained unmethylated. HeLa cells, derived from a cervical adenocarcinoma, contain chromosomally integrated HPV-18 genomes. We found that L1 is hypermethylated in these cells, while the LCR and E6 are unmethylated. Treatment of HeLa cells with the methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) led to the expected reduction of L1 methylation. After removal of 5-Aza-CdR, L1 methylation resumed and exceeded pretreatment levels. Unexpectedly, the LCR and E6 also became methylated under these conditions, albeit at lower levels than L1. We hypothesize that L1 is preferentially methylated after integration of the HPV genome into the cellular DNA, possibly since linearization prohibits its normal transcription, while the enhancer and promoter may be protected from methylation by transcription factors. Since our data suggest that HPV-18 L1 methylation can only be detected in carcinomas, except in some few precancerous lesions and asymptomatic infections, L1 methylation may constitute a powerful molecular marker for detecting this important step of neoplastic progression.

Azacitidine↗

PubMed2001

Regulation of neuronal cholecystokinin gene transcription.

Cholecystokinin (CCK) is a neuroendocrine peptide expressed in I-cells of the small intestine and in central and peripheral neurons. Whereas intestinal CCK is involved in the release of pancreatic enzymes and the contraction of the gallbladder, cerebral CCK is implicated in a variety of functions, such as feeding behaviour, anxiety and memory. The expression of CCK is developmentally regulated. Brain CCK mRNA levels are low before birth, but increase markedly shortly after birth and reach adult like patterns of expression three weeks after birth during the final maturation of the central nervous system. In the adult, several substances induce neuronal CCK mRNA expression via activation of transcription factors binding to regulatory elements in the CCK promoter. Recent studies have examined the signaling pathways, transcription factors and regulatory elements involved in cAMP, fibroblast growth factor-2, and calcium-induced CCK gene transcription in neuronal cells. The review describes the signaling pathways and transcription factors involved in neuronal CCK gene transcription.

Animals↗

PubMed2006

VIP is a transcriptional target of Nurr1 in dopaminergic cells.

The orphan nuclear receptor Nurr1 is required for the development of the ventral mesencephalic dopaminergic neurons. These are the same neurons that are invariantly lost in patients with Parkinson's disease. Nurr1 mRNA expression is not confined to the developing midbrain, and yet Nurr1 appears to be essential for either the maturation of progenitors into fully post-mitotic dopaminergic neurons and/or once formed, their survival. The function of Nurr1 in the transactivation of gene(s) important for neuronal development and/or maintenance is uncharacterized. To characterize potential downstream target genes of Nurr1, we sought to identify mRNAs that are differentially affected by Nurr1 expression. Using a dopaminergic cell line in which Nurr1 content was tightly regulated, differential display analysis identified transcripts altered by Nurr1 expression, including the mRNA encoding vasoactive intestinal peptide (VIP). Herein, we demonstrate that Nurr1 regulates VIP mRNA and protein levels, and transactivates the VIP promoter through Nurr1-responsive cis elements. In addition, dopaminergic cells release and utilize VIP to mediate survival when challenged with paraquat. Nurr1 regulation of VIP is also demonstrated in vivo as loss of Nurr1 function results in diminished VIP mRNA levels within the developing midbrain.

Animals↗

PubMed2006

CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.

Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture (3C) and fluorescence in situ hybridization, we found that one allele of the insulin-like growth factor 2 (Igf2)/H19 imprinting control region (ICR) on chromosome 7 colocalized with one allele of Wsb1/Nf1 on chromosome 11. Omission of CCCTC-binding factor (CTCF) or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. These findings demonstrate that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provide a model for long-range allele-specific associations between gene regions on different chromosomes that suggest a framework for DNA recombination and RNA trans-splicing.

Alleles↗

PubMed2006

A distal conserved sequence element controls Ifng gene expression by T cells and NK cells.

Chromatin dynamics that regulate Ifng gene expression are incompletely understood. By using cross-species comparative sequence analyses, we have identified conserved noncoding sequences (CNSs) upstream of the Ifng gene, one of which, located -22 kb from the transcriptional start site, contains clustered consensus binding sequences of transcription factors that function in T cell differentiation. CNS-22 was uniquely associated with histone modifications typical of accessible chromatin in both T helper 1 (Th1) and Th2 cells and demonstrated significant and selective T-bet (T-box transcription factor expressed in T cells, Tbx21)-dependent binding and enhancer activity in Th1 cells. Deletion of CNS-22 in the context of an Ifng reporter transgene ablated T cell receptor-dependent and -independent Ifng expression in Th1 effectors and similarly blocked expression by cytotoxic T lymphocytes and natural killer cells. Thus, a single distal element may be essential for Ifng gene expression by both innate and adaptive immune effector cell lineages.

Animals↗

PubMed2006

Mutations in the MYB intron I regulatory sequence increase transcription in colon cancers.

Although MYB overexpression in colorectal cancer (CRC) is known to be a prognostic indicator for poor survival, the basis for this overexpression is unclear. Among multiple levels of MYB regulation, the most dynamic is the control of transcriptional elongation by sequences within intron 1. The authors have proposed that this regulatory sequence is transcribed into an RNA stem-loop and 19-residue polyuridine tract, and is subject to mutation in CRC. When this region was examined in colorectal and breast carcinoma cell lines and tissues, the authors found frequent mutations only in CRC. It was determined that these mutations allowed increased transcription compared with the wild type sequence. These data suggest that this MYB regulatory region within intron 1 is subject to mutations in CRC but not breast cancer, perhaps consistent with the mutagenic insult that occurs within the colon and not mammary tissue. In CRC, these mutations may contribute to MYB overexpression, highlighting the importance of noncoding sequences in the regulation of key cancer genes.

3' Untranslated Regions↗

PubMed2005

Transforming growth factor-beta-regulated gene transcription and protein expression in human GFAP-negative lamina cribrosa cells.

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy, which is a major cause of worldwide visual impairment and blindness. Pathological hallmarks of the glaucomatous optic nerve head (ONH) include retinal ganglion cell axon loss and extracellular matrix (ECM) remodeling of the lamina cribrosa layer. Transforming growth factor-beta (TGF-beta) is an important pro-fibrotic modulator of ECM metabolism, whose levels are elevated in human POAG lamina cribrosa tissue compared with non-glaucomatous controls. We hypothesize that in POAG, lamina cribrosa (LC) glial cells respond to elevated TGF-beta, producing a remodeled ONH ECM. Using Affymetrix microarrays, we report the first study examining the effect of TGF-beta1 on global gene expression profiles in glial fibrillary acidic acid (GFAP)-negative LC glial cells in vitro. Prominent among the differentially expressed genes were those with established fibrogenic potential, including CTGF, collagen I, elastin, thrombospondin, decorin, biglycan, and fibromodulin. Independent TaqMan and Sybr Green quantitative PCR analysis significantly validated genes involved in regulation of cell proliferation (platelet-derived growth factor [PDGF-alpha]), angiogenesis (vascular endothelial growth factor [VEGF]), ECM accumulation and degradation (CTGF, IL-11, and ADAMT-S5), and growth factor binding (ESM-1). Bioinformatic analysis of the ESM-1 promoter identified putative Smad and Runx transcription factor binding sites, and luciferase assays confirmed that TGF-beta1 drives transcription of the ESM-1 gene. TGF-beta1 induces expression and release of ECM components in LC cells, which may be important in regulating matrix remodeling in the lamina cribrosa. In disease states such as POAG, the LC cell may represent an important pro-fibrotic cell type and an attractive target for novel therapeutic strategies.

Cells, Cultured↗

PubMed2005

Thrombopoietin regulates IEX-1 gene expression through ERK-induced AML1 phosphorylation.

The extracellular signal-regulated kinases (ERKs) are required for thrombopoietin (TPO) functions on hematopoietic cells, but the ERKs targets involved remain unknown. Here we show that the regulation of the immediate early gene X-1 (IEX-1), identified as an ERK substrate in response to TPO, was mediated by an ERK-dependent phosphorylation of AML1. The addition of TPO to UT7-Mpl cells and primary megakaryocytes induced gene expression of IEX-1. Neither erythropoietin (EPO) nor granulocyte macrophage-colony stimulating factor (GM-CSF) was able to activate IEX-1 gene expression in UT7-Mpl cells. The induced expression was mediated by a transcriptional activation of the IEX-1 promoter and required an AML1-binding site located at -1068. The direct involvement of AML1 in the regulation of IEX-1 gene expression was shown by both the use of AML1 mutants and by shRNA experiments targeting endogenous AML1. Finally, the ability of TPO to induce the IEX-1 gene expression was inhibited by U0126, a specific inhibitor of the ERKs activator MEK and AML1 transcriptional activity was shown to be modulated by TPO through ERK-dependent phosphorylation. Taken together, these data suggest that AML1 plays a role in modulating the IEX-1 expression and that the ERK-dependent AML1 phosphorylation regulates the TPO-mediated activation of IEX-1.

Apoptosis Regulatory Proteins↗

PubMed2006

Stubb: a program for discovery and analysis of cis-regulatory modules.

Given the DNA-binding specificities (motifs) of one or more transcription factors, an important bioinformatics problem is to discover significant clusters of binding sites for the transcription factors(s). Such clusters often correspond to cis-regulatory modules mediating regulation of an adjacent gene. In earlier work, we developed the Stubb program that uses a probabilistic model and a maximum likelihood approach to efficiently detect cis-regulatory modules over genomic scales. It may optionally exploit a second related genome to improve module prediction accuracy. We describe here the use of a web-based interface for the Stubb program. The interface is equipped with a special post-processing step for in-depth analysis of specific modules, in order to reveal individual binding sites predicted in the module. The web server may be accessed at the URL http://stubb.rockefeller.edu/.

Algorithms↗

PubMed2006

Nitric oxide transcriptionally down-regulates specific isoforms of divalent metal transporter (DMT1) via NF-kappaB.

Studies were performed to examine the affect of nitric oxide (NO) on expression of the divalent metal transporter (DMT1) in undifferentiated P19 embryonic carcinoma cells. DMT1 has four known isoforms which differ in both the N- and C-terminals. Results demonstrate that exposure of P19 cells to the NO precursor, sodium nitro-prusside (SNP), resulted in a decrease in expression of both positive (+) and negative (-) IRE isoforms of DMT1 with no change in the 1A species. Regulation was not as a result of decreased stability of message but was caused by reduction in transcription of the DMT1 1B isoforms. Similar results were observed in other cell lines, including PC12 and SH-SY5Y cells and rat primary sympathetic neurons. Nuclear NF-kappaB was decreased after SNP treatment, suggesting that NF-kappaB may mediate this response. Luciferase reporter assays with normal and NF-kappaB mutated constructs of the 1B promoter confirm that the NF-kappaB site between -23 to -19 upstream from the transcription start site was responsible for regulating expression. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays further demonstrate that the p65 subunit of NF-kappaB and not p50 binding is specifically decreased by NO treatment. Results of these studies provide a general mechanism responsible for regulating DMT1 expression induced by stress-related signaling processes in vivo.

Animals↗

PubMed2003

Exploring potential target genes of signaling pathways by predicting conserved transcription factor binding sites.

Many cellular signaling pathways induce gene expression by activating specific transcription factor complexes. Conventional approaches to the prediction of transcription factor binding sites lead to a notoriously high number of false discoveries. To alleviate this problem, we consider only binding sites that are conserved in man-mouse genomic sequence comparisons. We employ two alternative methods for predicting binding sites: exact matches to validated binding site sequences and weight matrix scans. We then ask the question whether there is a characteristic association between a transcription factor or set thereof to a particular group of genes. Our approach is tested on genes, which are induced in dendritic cells in response to the cells' exposure to LPS. We chose this example because the underlying signaling pathways are well understood. We demonstrate the benefit of conserved predicted binding sites in interpreting the LPS experiment. Additionally, we find that both methods for the prediction of conserved binding sites complement one another. Finally, our results suggest a distinct role for SRF in the context of LPS-induced gene expression.

Algorithms↗