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1
NEGI, Sarita, Saurabh K. SINGH, Nirupma PATI, Vikas HANDA, Ruchi CHAUHAN, and Uttam PATI. "A proximal tissue-specific module and a distal negative regulatory module control apolipoprotein(a) gene transcription." Biochemical Journal 379, no. 1 (2004): 151–59. http://dx.doi.org/10.1042/bj20030985.
Texte intégralRésumé :
The apo(a) [apolipoprotein(a)] gene is responsible for variations in plasma lipoprotein(a), high levels of which are a risk factor for atherosclerosis and myocardial infarction. The apo(a) promoter stimulates the expression of reporter genes in HepG2 cells, but not in HeLa cells. In the present study, we demonstrate that the 1.4 kb apo(a) promoter comprises two composite regulatory regions: a distal negative regulatory module (positions −1432 to −716) and a proximal tissue-specific module (−716 to −616). The distal negative regulatory module contains two strong negative regulatory regions [polymorphic PNR (pentanucleotide repeat region) and NREβ (negative regulatory element β)], which sandwich the postive regulatory region PREβ (positive regulatory element β). The PNR was shown to bind to transcription factors in a tissue-specific manner, whereas the ubiquitous transcription factors hepatocyte nuclear factor 3α and GATA binding protein 4 bound to NREβ to repress gene transcription. The proximal tissue-specific module contains two regulatory elements: an activating region (PREα) that activates transcription in HepG2 cells, and NREα, which is responsible for repressing the apo(a) gene in HeLa cells. NREα binds to a HeLa-specific repressor. These multiple regulatory elements might work co-operatively to finely regulate apo(a) gene expression. Although the tissue-specific module is required for apo(a) gene activation and repression in a tissue-specific manner, the combinatorial interplay of the distal and proximal regulators might define the complex pathway(s) of apo(a) gene regulation.
2
Herbomel, P., A. Rollier, F. Tronche, M. O. Ott, M. Yaniv, and M. C. Weiss. "The rat albumin promoter is composed of six distinct positive elements within 130 nucleotides." Molecular and Cellular Biology 9, no. 11 (1989): 4750–58. http://dx.doi.org/10.1128/mcb.9.11.4750-4758.1989.
Texte intégralRésumé :
No fewer than six different positive regulatory elements concentrated within 130 base pairs constitute the rat albumin promoter, which drives highly tissue specific transcription in rat hepatoma cells in culture. Inactivation of each element led to a decrease in transcriptional efficiency: from upstream to downstream, 3- to 4-fold for distal elements III and II, 15-fold for distal element I, and 50-fold for the CCAAT box and the proximal element (PE). Three of these elements, distal elements III and II and, more crucially, the PE, were found to be involved in the tissue-specific character of transcription, with an additional negative regulation possibly superimposed at the level of the PE. Finally, our mapping of these regulatory elements in vivo entirely coincided with footprint data obtained in vitro, thereby allowing the tentative assignment of specific factors to the effects observed in vivo.
3
Herbomel, P., A. Rollier, F. Tronche, M. O. Ott, M. Yaniv, and M. C. Weiss. "The rat albumin promoter is composed of six distinct positive elements within 130 nucleotides." Molecular and Cellular Biology 9, no. 11 (1989): 4750–58. http://dx.doi.org/10.1128/mcb.9.11.4750.
Texte intégralRésumé :
No fewer than six different positive regulatory elements concentrated within 130 base pairs constitute the rat albumin promoter, which drives highly tissue specific transcription in rat hepatoma cells in culture. Inactivation of each element led to a decrease in transcriptional efficiency: from upstream to downstream, 3- to 4-fold for distal elements III and II, 15-fold for distal element I, and 50-fold for the CCAAT box and the proximal element (PE). Three of these elements, distal elements III and II and, more crucially, the PE, were found to be involved in the tissue-specific character of transcription, with an additional negative regulation possibly superimposed at the level of the PE. Finally, our mapping of these regulatory elements in vivo entirely coincided with footprint data obtained in vitro, thereby allowing the tentative assignment of specific factors to the effects observed in vivo.
4
Collins, Patrick, Melodie Henderson, Shojing Chang, et al. "Distal regions of the human IFNG locus direct cell-type specific expression (88.12)." Journal of Immunology 184, no. 1_Supplement (2010): 88.12. http://dx.doi.org/10.4049/jimmunol.184.supp.88.12.
Texte intégralRésumé :
Abstract Genes, such as IFNG, which are expressed in multiple cell lineages of the immune system, may employ a common set of regulatory elements to direct transcription in multiple cell types or individual regulatory elements to direct expression in individual cell lineages. By employing a BAC transgenic system, we demonstrate that IFNG employs unique regulatory elements to achieve lineage specific transcriptional control. Specifically, a one 1-kb element 30 kb upstream of IFNG activates transcription in T cells and NKT cells but not NK cells, macrophages and dendritic cells. This distal regulatory element is a Runx3 binding site in Th1 cells, and is needed for RNA polymerase II recruitment to IFNG, but not for histone acetylation of the IFNG locus. These results support a model whereby IFNG utilizes distinct regulatory elements to achieve cell-type expression.
5
Mangnier, Loïc, Charles Joly-Beauparlant, Arnaud Droit, Steve Bilodeau, and Alexandre Bureau. "Cis-regulatory hubs: a new 3D model of complex disease genetics with an application to schizophrenia." Life Science Alliance 5, no. 5 (2022): e202101156. http://dx.doi.org/10.26508/lsa.202101156.
Texte intégralRésumé :
The 3D conformation of the chromatin creates complex networks of noncoding regulatory regions (distal elements) and promoters impacting gene regulation. Despite the importance of the role of noncoding regions in complex diseases, little is known about their interplay within regulatory hubs and implication in multigenic diseases such as schizophrenia. Here we show that cis-regulatory hubs (CRHs) in neurons highlight functional interactions between distal elements and promoters, providing a model to explain epigenetic mechanisms involved in complex diseases. CRHs represent a new 3D model, where distal elements interact to create a complex network of active genes. In a disease context, CRHs highlighted strong enrichments in schizophrenia-associated genes, schizophrenia-associated SNPs, and schizophrenia heritability compared with equivalent structures. Finally, CRHs exhibit larger proportions of genes differentially expressed in schizophrenia compared with promoter-distal element pairs or TADs. CRHs thus capture causal regulatory processes improving the understanding of complex disease etiology such as schizophrenia. These multiple lines of genetic and statistical evidence support CRHs as 3D models to study dysregulation of gene expression in complex diseases more generally.
6
Müller, Patrick, Kenneth W. Merrell, Justin D. Crofts, et al. "Estrogen-dependent downregulation of hairy and enhancer of split homolog-1 gene expression in breast cancer cells is mediated via a 3′ distal element." Journal of Endocrinology 200, no. 3 (2008): 311–19. http://dx.doi.org/10.1677/joe-08-0094.
Texte intégralRésumé :
Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5′ promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3′ region, an estrogen receptor α(ER)α binding site. The ERα binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERα binding and transcriptional regulation. Chromatin immunoprecipitation assays revealed that ERα is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3′ region of the HES-1 gene.
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Tsika, Richard W., John McCarthy, Natalia Karasseva, Yangsi Ou та Gretchen L. Tsika. "Divergence in species and regulatory role of β-myosin heavy chain proximal promoter muscle-CAT elements". American Journal of Physiology-Cell Physiology 283, № 6 (2002): C1761—C1775. http://dx.doi.org/10.1152/ajpcell.00278.2002.
Texte intégralRésumé :
We examined the functional role of distinct muscle-CAT (MCAT) elements during non-weight-bearing (NWB) regulation of a wild-type 293-base pair β-myosin heavy chain (βMyHC) transgene. Electrophoretic mobility shift assays (EMSA) revealed decreased NTEF-1, poly(ADP-ribose) polymerase, and Max binding at the human distal MCAT element when using NWB soleus vs. control soleus nuclear extract. Compared with the wild-type transgene, expression assays revealed that distal MCAT element mutation decreased basal transgene expression, which was decreased further in response to NWB. EMSA analysis of the human proximal MCAT (pMCAT) element revealed low levels of NTEF-1 binding that did not differ between control and NWB extract, whereas the rat pMCAT element displayed robust NTEF-1 binding that decreased when using NWB soleus extracts. Differences in binding between human and rat pMCAT elements were consistent whether using rat or mouse nuclear extract or in vitro synthesized human TEF-1 proteins. Our results provide the first evidence that 1) different binding properties and likely regulatory functions are served by the human and rat pMCAT elements, and 2) previously unrecognized βMyHC proximal promoter elements contribute to NWB regulation.
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Li, Youlin, Yutaka Okuno, Pu Zhang, et al. "Regulation of the PU.1 gene by distal elements." Blood 98, no. 10 (2001): 2958–65. http://dx.doi.org/10.1182/blood.v98.10.2958.
Texte intégralRésumé :
Abstract The transcription factor PU.1 (also known as Spi-1) plays a critical role in the development of the myeloid lineages, and myeloid cells derived from PU.1−/− animals are blocked at the earliest stage of myeloid differentiation. Expression of the PU.1 gene is tightly regulated during normal hematopoietic development, and dysregulation of PU.1 expression can lead to erythroleukemia. However, relatively little is known about how the PU.1 gene is regulated in vivo. Here it is shown that myeloid cell type–specific expression of PU.1 in stable cell lines and transgenic animals is conferred by a 91-kilobase (kb) murine genomic DNA fragment that consists of the entire PU.1 gene (20 kb) plus approximately 35 kb of upstream and downstream sequences, respectively. To further map the important transcriptional regulatory elements, deoxyribonuclease I hypersensitive site mapping studies revealed at least 3 clusters in the PU.1 gene. A 3.5-kb fragment containing one of these deoxyribonuclease I hypersensitive sites, located −14 kb 5′ of the transcriptional start site, conferred myeloid cell type–specific expression in stably transfected cell lines, suggesting that within this region is an element important for myeloid specific expression of PU.1. Further analysis of this myeloid-specific regulatory element will provide insight into the regulation of this key transcriptional regulator and may be useful as a tool for targeting expression to the myeloid lineage.
9
Maghsoudlou, Sepehr Steve, Timothy R. Hughes, and Peter J. Hornsby. "Analysis of the distal 5′ region of the humanCYP17gene." Genome 38, no. 5 (1995): 845–49. http://dx.doi.org/10.1139/g95-111.
Texte intégralRésumé :
In order to search for additional regulatory elements in the human CYP17 (steroid 17α-hydroxylase) gene and to compare it with potential regulatory elements in bovine CYP17 genes, 3.5 kb of 5′ flanking region of CYP17 was cloned and analyzed. The newly acquired sequence was shown to be a highly defective copy of the human endogenous retrovirus HERV-K family. This retroviral sequence was itself interrupted by a novel element, a low copy number repeat occurring about 20 times in the human genome, including a known copy in the human catechol-O-methyltransferase gene. A reanalysis of the entire 5′ flanking region of human CYP17 indicates that only the 300 bp immediately distal to the promoter is of unique sequence; other regulatory sequences, including any that are similar to the upstream region of the bovine genes, are unlikely to occur within 5.5 kb of the promoter.Key words: Human CYP17 gene, endogenous retrovirus, low-copy-number repeats.
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Tapscott, S. J., A. B. Lassar, and H. Weintraub. "A novel myoblast enhancer element mediates MyoD transcription." Molecular and Cellular Biology 12, no. 11 (1992): 4994–5003. http://dx.doi.org/10.1128/mcb.12.11.4994-5003.1992.
Texte intégralRésumé :
The MyoD gene can orchestrate the expression of the skeletal muscle differentiation program. We have identified the regions of the gene necessary to reproduce transcription specific to skeletal myoblasts and myotubes. A proximal regulatory region (PRR) contains a conserved TATA box, a CCAAT box, and a GC-rich region that includes a consensus SP1 binding site. The PRR is sufficient for high levels of skeletal muscle-specific activity in avian muscle cells. In murine cells the PRR alone has only low levels of activity and requires an additional distal regulatory region to achieve high levels of muscle-specific activity. The distal regulatory region differs from a conventional enhancer in that chromosomal integration appears necessary for productive interactions with the PRR. While the Moloney leukemia virus long terminal repeat can enhance transcription from the MyoD PRR in both transient and stable assays, the simian virus 40 enhancer cannot, suggesting that specific enhancer-promoter interactions are necessary for PRR function.
11
Tapscott, S. J., A. B. Lassar, and H. Weintraub. "A novel myoblast enhancer element mediates MyoD transcription." Molecular and Cellular Biology 12, no. 11 (1992): 4994–5003. http://dx.doi.org/10.1128/mcb.12.11.4994.
Texte intégralRésumé :
The MyoD gene can orchestrate the expression of the skeletal muscle differentiation program. We have identified the regions of the gene necessary to reproduce transcription specific to skeletal myoblasts and myotubes. A proximal regulatory region (PRR) contains a conserved TATA box, a CCAAT box, and a GC-rich region that includes a consensus SP1 binding site. The PRR is sufficient for high levels of skeletal muscle-specific activity in avian muscle cells. In murine cells the PRR alone has only low levels of activity and requires an additional distal regulatory region to achieve high levels of muscle-specific activity. The distal regulatory region differs from a conventional enhancer in that chromosomal integration appears necessary for productive interactions with the PRR. While the Moloney leukemia virus long terminal repeat can enhance transcription from the MyoD PRR in both transient and stable assays, the simian virus 40 enhancer cannot, suggesting that specific enhancer-promoter interactions are necessary for PRR function.
12
Laverré, Alexandre, Eric Tannier, and Anamaria Necsulea. "Long-range promoter–enhancer contacts are conserved during evolution and contribute to gene expression robustness." Genome Research 32, no. 2 (2021): 280–96. http://dx.doi.org/10.1101/gr.275901.121.
Texte intégralRésumé :
Gene expression is regulated through complex molecular interactions, involving cis-acting elements that can be situated far away from their target genes. Data on long-range contacts between promoters and regulatory elements are rapidly accumulating. However, it remains unclear how these regulatory relationships evolve and how they contribute to the establishment of robust gene expression profiles. Here, we address these questions by comparing genome-wide maps of promoter-centered chromatin contacts in mouse and human. We show that there is significant evolutionary conservation of cis-regulatory landscapes, indicating that selective pressures act to preserve not only regulatory element sequences but also their chromatin contacts with target genes. The extent of evolutionary conservation is remarkable for long-range promoter–enhancer contacts, illustrating how the structure of regulatory landscapes constrains large-scale genome evolution. We show that the evolution of cis-regulatory landscapes, measured in terms of distal element sequences, synteny, or contacts with target genes, is significantly associated with gene expression evolution.
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Wildin, R. S., H. U. Wang, K. A. Forbush, and R. M. Perlmutter. "Functional dissection of the murine lck distal promoter." Journal of Immunology 155, no. 3 (1995): 1286–95. http://dx.doi.org/10.4049/jimmunol.155.3.1286.
Texte intégralRésumé :
Abstract The lymphocyte-specific proto-oncogene lck is transcribed from two developmentally regulated, independently functioning promoters. The proximal promoter is used in thymocytes, but not in peripheral T lymphocytes. The distal promoter operates in all stages of T cell development, but predominates in more mature cells. Both promoters lack a TATAA element and they share little sequence similarity with each other. Using transgenic mice to locate in vivo functional cis-acting regions of the murine distal promoter, we defined a region from -1786 to -2913 that is essential for consistent insertion site-independent expression of a heterologous cDNA reporter. The transgene is lymphoid specific and expressed predominantly in T cells. One of four transgenic mice bearing a shortened distal promoter (-886 to +41) expressed the reporter in the expected developmental pattern, suggesting that important regulatory elements that require favorable flanking sequences for expression are present nearer the transcription start site. The DNA sequence from -4032 to +623 contains few consensus binding sites for previously described T lymphocyte-specific trans-acting factors, and their locations do not correlate well with the functional data. However, the locations of tissue-specific modifications of chromatin structure in the promoter region, manifest as sites of DNase hypersensitivity, correlated with these two functional regions in normal mice. The identification of lck distal promoter regulatory regions provides a useful control element for deliberate expression of transgenes in mature T lymphocytes. In addition, these regulatory regions should assist in defining T cell-specific trans-acting factors.
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Ayer, S., and C. Benyajati. "Conserved enhancer and silencer elements responsible for differential Adh transcription in Drosophila cell lines." Molecular and Cellular Biology 10, no. 7 (1990): 3512–23. http://dx.doi.org/10.1128/mcb.10.7.3512-3523.1990.
Texte intégralRésumé :
The distal promoter of Adh is differentially expressed in Drosophila tissue culture cell lines. After transfection with an exogenous Adh gene, there was a specific increase in distal alcohol dehydrogenase (ADH) transcripts in ADH-expressing (ADH+) cells above the levels observed in transfected ADH-nonexpressing (ADH-) cells. We used deletion mutations and a comparative transient-expression assay to identify the cis-acting elements responsible for enhanced Adh distal transcription in ADH+ cells. DNA sequences controlling high levels of distal transcription were localized to a 15-base-pair (bp) region nearly 500 bp upstream of the distal RNA start site. In addition, a 61-bp negative cis-acting element was found upstream from and adjacent to the enhancer. When this silencer element was deleted, distal transcription increased only in the ADH+ cell line. These distant upstream elements must interact with the promoter elements, the Adf-1-binding site and the TATA box, as they only influenced transcription when at least one of these two positive distal promoter elements was present. Internal deletions targeted to the Adf-1-binding site or the TATA box reduced transcription in both cell types but did not affect the transcription initiation site. Distal transcription in transfected ADH- cells appears to be controlled primarily through these promoter elements and does not involve the upstream regulatory elements. Evolutionary conservation in distantly related Drosophila species suggests the importance of these upstream elements in correct developmental and tissue-specific expression of ADH.
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Ayer, S., and C. Benyajati. "Conserved enhancer and silencer elements responsible for differential Adh transcription in Drosophila cell lines." Molecular and Cellular Biology 10, no. 7 (1990): 3512–23. http://dx.doi.org/10.1128/mcb.10.7.3512.
Texte intégralRésumé :
The distal promoter of Adh is differentially expressed in Drosophila tissue culture cell lines. After transfection with an exogenous Adh gene, there was a specific increase in distal alcohol dehydrogenase (ADH) transcripts in ADH-expressing (ADH+) cells above the levels observed in transfected ADH-nonexpressing (ADH-) cells. We used deletion mutations and a comparative transient-expression assay to identify the cis-acting elements responsible for enhanced Adh distal transcription in ADH+ cells. DNA sequences controlling high levels of distal transcription were localized to a 15-base-pair (bp) region nearly 500 bp upstream of the distal RNA start site. In addition, a 61-bp negative cis-acting element was found upstream from and adjacent to the enhancer. When this silencer element was deleted, distal transcription increased only in the ADH+ cell line. These distant upstream elements must interact with the promoter elements, the Adf-1-binding site and the TATA box, as they only influenced transcription when at least one of these two positive distal promoter elements was present. Internal deletions targeted to the Adf-1-binding site or the TATA box reduced transcription in both cell types but did not affect the transcription initiation site. Distal transcription in transfected ADH- cells appears to be controlled primarily through these promoter elements and does not involve the upstream regulatory elements. Evolutionary conservation in distantly related Drosophila species suggests the importance of these upstream elements in correct developmental and tissue-specific expression of ADH.
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Majumder, Kinjal, Olivia I. Koues, Elizabeth A. W. Chan, et al. "Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element." Journal of Experimental Medicine 212, no. 1 (2014): 107–20. http://dx.doi.org/10.1084/jem.20141479.
Texte intégralRésumé :
Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unknown. We identify a novel mechanism by which cis-elements promote long-range interactions, inducing conformational changes critical for diversification of the TCRβ antigen receptor locus (Tcrb). Association between distal Vβ gene segments and the highly expressed DβJβ clusters, termed the recombination center (RC), is independent of enhancer function and recruitment of V(D)J recombinase. Instead, we find that tissue-specific folding of Tcrb relies on two distinct architectural elements located upstream of the RC. The first, a CTCF-containing element, directly tethers distal portions of the Vβ array to the RC. The second element is a chromatin barrier that protects the tether from hyperactive RC chromatin. When the second element is removed, active RC chromatin spreads upstream, forcing the tether to serve as a new barrier. Acquisition of barrier function by the CTCF element disrupts contacts between distal Vβ gene segments and significantly alters Tcrb repertoires. Our findings reveal a separation of function for RC-flanking regions, in which anchors for long-range recombination must be cordoned off from hyperactive RC landscapes by chromatin barriers.
17
Zhu, A., and M. A. Kuziora. "Functional domains in the Deformed protein." Development 122, no. 5 (1996): 1577–87. http://dx.doi.org/10.1242/dev.122.5.1577.
Texte intégralRésumé :
A chimeric protein consisting of Deformed with a substituted Abdominal-B homeodomain (Dfd/Abd-B) is used to identify protein domains outside the homeodomain that are required for regulatory activity in vivo. A series of deletion proteins were generated based on regions showing amino acid composition similar to known regulatory domains. Each mutant protein can influence regulation of homeotic genes in a manner distinct from the intact protein. Activity was also tested using promoter elements from empty spiracles and Distal-less, two genes known to be directly regulated by Abdominal-B. Removal of the acidic region and the C-tail region convert the chimera from a strong activator to a repressor of the Distal-less element, but had comparatively little effect on the activation of the empty spiracles element. Constructs without a third domain, the N domain, fail to show any regulatory activity. The N domain is the only domain of the Dfd/Abd-B protein which exhibits significant activation activity when fused to a heterologous DNA binding domain. Our results suggest transcriptional activity of the N domain can be modulated by the acidic and C-tail domains.
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Cichocki, Frank, Rebecca J. Hanson, Todd Lenvik, et al. "The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element." Blood 113, no. 14 (2009): 3245–53. http://dx.doi.org/10.1182/blood-2008-07-166389.
Texte intégralRésumé :
Abstract The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5′ promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education.
19
LACORTE, Jean-Marc, Esther FOURNIAT, Danièle PASTIER, Jean CHAMBAZ, Agnès RIBEIRO, and Philippe CARDOT. "The proximal element of the human apolipoprotein A-II promoter increases the enhancer activity of the distal region." Biochemical Journal 318, no. 2 (1996): 681–88. http://dx.doi.org/10.1042/bj3180681.
Texte intégralRésumé :
We have previously shown that human apolipoprotein A-II (apoA-II) transcription is controlled by a complex set of regulatory elements. In this study, we demonstrate that the distal region of the apoA-II promoter (-911/-614) acts as an enhancer and results in a 6-fold increase in activity when the proximal AB element is inserted between this enhancer and a TATA box. The AB element alone does not display any transcriptional activity. The combination of the proximal AB element and the enhancer is sufficient to activate transcription to the same level as that achieved with the full-length promoter. DNA binding and competition assays, and binding interference experiments allowed us to identify two adjacent binding sites within the AB element. These bind activities designated CIIIB1 and AIIAB3/4, respectively. Mutation on each of these sites showed that the binding site of CIIIB1 within the AB element played a major role in the interaction with the enhancer. Whereas transcriptional activation of other apolipoprotein genes involves the binding of the liver-enriched hepatocyte nuclear factor 4 (HNF4) on their proximal promoter, the present study demonstrates that neither HNF4 nor ApoA-I regulatory protein 1, its antagonistic orphan receptor, was able to bind the AB element. Instead, apoA-II transcription was driven by the interaction of apoA-II enhancer with proximal AB element, which involves an unidentified activity, CIIIB1.
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Levantini, Elena, Yutaka Okuno, Pu Zhang, et al. "3′ Distal Regulatory Elements Required for Human CD34 Expression in Transgenic Mice." Blood 106, no. 11 (2005): 125. http://dx.doi.org/10.1182/blood.v106.11.125.125.
Texte intégralRésumé :
Abstract CD34 is the best-defined human hematopoietic stem cell (HSC) marker, however the regulation of its gene expression is still largely unknown. Therefore, unraveling the elements that regulate human CD34 expression would be an invaluable tool for a broad range of studies, including the establishment of models of leukemia in mice, which require targeting of the transgene to stem and/or early progenitor cells. Moreover, identification of such regulatory elements will provide important insights into the transcriptional agenda of stem and progenitor cells and most importantly will prove useful for gene therapy protocols. Studies from our laboratory demonstrated that human CD34 transgenes are expressed in murine repopulating HSCs, which resembles the expression of the CD34 gene in human hematopoiesis, thus indicating the mouse model as an excellent way to study the expression of human CD34. Using P1 derived artificial chromosome (PAC) clones encompassing the human CD34 gene to generate transgenic mice, we showed that 90kb of upstream and 26kb of downstream flanking sequences were capable of regulating human CD34 expression in murine transgenic lines. Successive deletions of this larger construct were then performed to identify the important control regions. Deletion of the 5′ region from −90kb to −18kb did not result in any loss of activity. PAC54A19, a clone extending from −18kb to +26kb, expressed RNA in various tissues in a manner similar to that of larger fragments. In contrast, deletions creating a construct spanning from −10kb to +17kb led to complete loss of expression in transgenic animals, indicating that critical distal elements are located between −18kb to −10kb and/or +17kb to +26kb. In order to facilitate identification of important regulatory elements present in the upstream (−18kb to −10 kb) and/or downstream (+17kb to +26kb) regions of human CD34, we created further deletions of PAC54A19 using rare-cutting restriction enzymes, and studied the effects of the deletions on human CD34 expression in transgenic mice. Interestingly, we did not detect any human CD34 mRNA and protein expression in bone marrow and HSCs from transgenic mice carrying a construct spanning from −18kb to +17.4kb. In contrast, we observed expression of human CD34 transcripts in the bone marrow of transgenic mice containing a PAC spanning from −12.8kb to +26kb. Furthermore, HSCs from this latter group of mice presented the human CD34 antigen on their surface, as detected by FACS. Taken together, these data are highly suggestive that critical cis regulatory element(s) required to drive human CD34 in vivo expression are located in a 8.6kb fragment placed between +17.4kb and +26kb downstream of the human CD34 gene. Our current efforts focus on identifying the element(s) within the 8.6kb 3′ region that might be required to achieve human CD34 expression in HSCs.
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Ebralidze, Alexander K., Annalisa Di Ruscio, Sanghoon Lee, Karen O'Brien, and Daniel G. Tenen. "Epigenetic Control of C/EBPa by Distant Synergic Regulatory Elements." Blood 114, no. 22 (2009): 1470. http://dx.doi.org/10.1182/blood.v114.22.1470.1470.
Texte intégralRésumé :
Abstract Abstract 1470 Poster Board I-493 The transcription factor C/EBPa plays a pivotal role in hematopoietic stem cell (HSC) commitment and differentiation. Expression of the C/EBPa gene is tightly regulated during normal hematopoietic development, and dysregulation of C/EBPa expression can lead to lung cancer and leukemia. However, little is known about how the C/EBPa gene is regulated in vivo. In this study, we demonstrate synergetic regulation of C/EBPa by two distant cis-elemets located 5' and 3' to the gene and their effect on chromatin architecture. Previous studies have indicated that as much as 4.8 kb of 5' upstream C/EBPa regulatory sequences were unable to express significant levels of reporter gene activity in transgenic mice. Therefore, we initiated a search for important distal elements in the C/EBPa locus. We have applied a combination of 1) comparative analysis of human and mouse genomic sequences; 2) DNase I hypersensitive studies; 3) chromosome conformation capture (3C); 4) analysis of reporter constructs in stable cells lines; and 5) generation and analysis of transgenic mouse lines. This let us to identify the regulatory role of two distal conserved homology elements located at ∼38 kb 5' of the transcription start site (TSS) of murine C/EBPa (corresponding to ∼45 kb 5' of the TSS of human C/EBPa) and at ∼33 kb 3' to TSS of both murine and human C/EBPa. We show that the constructs lacking both distal elements were unable to express C/EBPa mRNA, while addition of each region resulted in detectable (by Northern blot analysis) expression in transgenic animals. We have observed a cooperative effect of these two regions on C/EBPa expression, a construct carrying both elements expresses ∼2.5-fold level over constructs carrying either one element alone. We have investigated the mechanism for the increased expression by these distal elements by using deletion constructs. Our results suggest that lack of these elements results in aberrant gene expression due to proximal promoter DNA hypermethylation and point to a novel mechanism in establishment of critical epigenetic marks. Disclosures: No relevant conflicts of interest to declare.
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Lu, Xi, Naga Prathyusha Maturi, Malin Jarvius, et al. "ECOA-7. Conserved cell-lineage controlled chromatin accessibility in human and mouse glioblastoma stem cells predicts functionally distinct subgroups." Neuro-Oncology Advances 3, Supplement_2 (2021): ii2. http://dx.doi.org/10.1093/noajnl/vdab070.007.
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Abstract There is ample support for developmental control of glioblastoma stem cells (GSCs), and a deeper knowledge of their epigenetic regulation could be central to more efficient glioblastoma (GBM) therapies. For this purpose, we analyzed the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered an epigenetic variability of both mouse and human GSC cultures that differed from transcriptome clusters. Both mouse and human chromatin accessibility-guided clusters were predominantly determined by distal regulatory elements, displayed unique sets of transcription factor motif enrichment, and exhibited different functional and drug-response properties. Cross-species analysis of distal regulatory element regions in accessible chromatin of mouse and human cultures revealed conserved epigenetic regulation of GSCs.
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Chung, Y. T., and E. B. Keller. "Positive and negative regulatory elements mediating transcription from the Drosophila melanogaster actin 5C distal promoter." Molecular and Cellular Biology 10, no. 12 (1990): 6172–80. http://dx.doi.org/10.1128/mcb.10.12.6172-6180.1990.
Texte intégralRésumé :
The major cytoskeletal actin gene of Drosophila melanogaster, the actin 5C gene, has two promoters, the distal one of which controls synthesis of actin in a tissue- and developmental stage-specific manner. This very strong promoter has widely been used for expression of heterologous genes in cultured cells. To locate functional regulatory elements in this distal promoter, mutants of the promoter were fused to the bacterial chloramphenicol acetyltransferase gene and assayed for transient expression activity in cultured Drosophila embryonic Schneider line 2 cells. The results showed that the upstream end of the promoter extends to 522 bp from the transcription start site. In addition, there are two remote activating regions about 2 kb upstream. Between -522 and -379 are two regions that exert a strong negative effect. Downstream from these negative regions are at least six positive regions and a TATA element. The strongest positive determinant of the promoter was identified at -320 as AAAATGTG by footprinting and by a replacement experiment. When the relevant region was replaced by a synthetic sequence containing this element in a random context, the transient expression activity was restored. The sequence TGTATG located at -355 was also identified as a positive element by a similar replacement approach. Apparently the very high activity of this promoter is the result of the combined activities of multiple factors.
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Chung, Y. T., and E. B. Keller. "Positive and negative regulatory elements mediating transcription from the Drosophila melanogaster actin 5C distal promoter." Molecular and Cellular Biology 10, no. 12 (1990): 6172–80. http://dx.doi.org/10.1128/mcb.10.12.6172.
Texte intégralRésumé :
The major cytoskeletal actin gene of Drosophila melanogaster, the actin 5C gene, has two promoters, the distal one of which controls synthesis of actin in a tissue- and developmental stage-specific manner. This very strong promoter has widely been used for expression of heterologous genes in cultured cells. To locate functional regulatory elements in this distal promoter, mutants of the promoter were fused to the bacterial chloramphenicol acetyltransferase gene and assayed for transient expression activity in cultured Drosophila embryonic Schneider line 2 cells. The results showed that the upstream end of the promoter extends to 522 bp from the transcription start site. In addition, there are two remote activating regions about 2 kb upstream. Between -522 and -379 are two regions that exert a strong negative effect. Downstream from these negative regions are at least six positive regions and a TATA element. The strongest positive determinant of the promoter was identified at -320 as AAAATGTG by footprinting and by a replacement experiment. When the relevant region was replaced by a synthetic sequence containing this element in a random context, the transient expression activity was restored. The sequence TGTATG located at -355 was also identified as a positive element by a similar replacement approach. Apparently the very high activity of this promoter is the result of the combined activities of multiple factors.
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Yuasa, Katsutoshi, and Takao Hijikata. "Distal regulatory element of theSTAT1gene potentially mediates positive feedback control of STAT1 expression." Genes to Cells 21, no. 1 (2015): 25–40. http://dx.doi.org/10.1111/gtc.12316.
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Czarnecka, E., J. L. Key, and W. B. Gurley. "Regulatory domains of the Gmhsp17.5-E heat shock promoter of soybean." Molecular and Cellular Biology 9, no. 8 (1989): 3457–63. http://dx.doi.org/10.1128/mcb.9.8.3457-3463.1989.
Texte intégralRésumé :
Promoter domains required for in vivo transcriptional expression of soybean heat shock gene Gmhsp17.5-E were identified by insertion-deletion mutagenesis with transgenic expression monitored in Agrobacterium tumefaciens-incited tumors of sunflower. Removal of the TATA-distal domain from position -1175 to position -259 had little effect on overall activity. The four regions contributing to promoter activity identified by this study all map within 244 base pairs from the start of transcription. The most distal cis-acting element of major significance was located from -244 to -179 and contains a conserved TATA-dyad motif centered at -220. Sequences from -179 to -40 comprise the TATA-proximal domain and include an AT-rich region and two sites containing heat shock consensus elements (HSEs). Deletion of the HSE centered at -93 (site 2) severely reduced transcriptional activity. Heat-inducible expression was also eliminated by internal deletion of either the TATA motif or the overlapping HSEs at site 1, indicating that each of these regions is also a major determinant of promoter activity.
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Czarnecka, E., J. L. Key, and W. B. Gurley. "Regulatory domains of the Gmhsp17.5-E heat shock promoter of soybean." Molecular and Cellular Biology 9, no. 8 (1989): 3457–63. http://dx.doi.org/10.1128/mcb.9.8.3457.
Texte intégralRésumé :
Promoter domains required for in vivo transcriptional expression of soybean heat shock gene Gmhsp17.5-E were identified by insertion-deletion mutagenesis with transgenic expression monitored in Agrobacterium tumefaciens-incited tumors of sunflower. Removal of the TATA-distal domain from position -1175 to position -259 had little effect on overall activity. The four regions contributing to promoter activity identified by this study all map within 244 base pairs from the start of transcription. The most distal cis-acting element of major significance was located from -244 to -179 and contains a conserved TATA-dyad motif centered at -220. Sequences from -179 to -40 comprise the TATA-proximal domain and include an AT-rich region and two sites containing heat shock consensus elements (HSEs). Deletion of the HSE centered at -93 (site 2) severely reduced transcriptional activity. Heat-inducible expression was also eliminated by internal deletion of either the TATA motif or the overlapping HSEs at site 1, indicating that each of these regions is also a major determinant of promoter activity.
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Searle, P. F., G. W. Stuart, and R. D. Palmiter. "Building a metal-responsive promoter with synthetic regulatory elements." Molecular and Cellular Biology 5, no. 6 (1985): 1480–89. http://dx.doi.org/10.1128/mcb.5.6.1480-1489.1985.
Texte intégralRésumé :
A fusion gene consisting of the promoter region from the mouse metallothionein-I gene joined to the coding region of the herpes simplex virus thymidine kinase gene is efficiently regulated by zinc in a transient assay when transfected into baby hamster kidney cells. Analysis of similar plasmids in which the metallothionein-I promoter region was mutated indicated the presence of multiple metal regulatory elements (MREs) between -176 and -44 base pairs from the cap site. To further investigate the function of MREs, we inserted a synthetic DNA fragment containing the sequence of MRE-a (the element between -55 and -44 base pairs) into the nonresponsive promoter of the thymidine kinase gene in various positions and configurations. Little or no induction by zinc was observed with single insertions of the regulatory sequence, whereas many different constructions having two copies of MRE-a were inducible. The precise position of the two MREs relative to each other or to the thymidine kinase promoter elements had a relatively small effect on the efficiency of induction, but the inducibility could be further increased by the introduction of more MRE-a sequences. MRE-a can function synergistically with the thymidine kinase distal promoter elements, but in the presence of the TATA box alone it functions as a positive, zinc-dependent promoter element.
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Searle, P. F., G. W. Stuart, and R. D. Palmiter. "Building a metal-responsive promoter with synthetic regulatory elements." Molecular and Cellular Biology 5, no. 6 (1985): 1480–89. http://dx.doi.org/10.1128/mcb.5.6.1480.
Texte intégralRésumé :
A fusion gene consisting of the promoter region from the mouse metallothionein-I gene joined to the coding region of the herpes simplex virus thymidine kinase gene is efficiently regulated by zinc in a transient assay when transfected into baby hamster kidney cells. Analysis of similar plasmids in which the metallothionein-I promoter region was mutated indicated the presence of multiple metal regulatory elements (MREs) between -176 and -44 base pairs from the cap site. To further investigate the function of MREs, we inserted a synthetic DNA fragment containing the sequence of MRE-a (the element between -55 and -44 base pairs) into the nonresponsive promoter of the thymidine kinase gene in various positions and configurations. Little or no induction by zinc was observed with single insertions of the regulatory sequence, whereas many different constructions having two copies of MRE-a were inducible. The precise position of the two MREs relative to each other or to the thymidine kinase promoter elements had a relatively small effect on the efficiency of induction, but the inducibility could be further increased by the introduction of more MRE-a sequences. MRE-a can function synergistically with the thymidine kinase distal promoter elements, but in the presence of the TATA box alone it functions as a positive, zinc-dependent promoter element.
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Besnard, Valérie, Yan Xu, and Jeffrey A. Whitsett. "Sterol response element binding protein and thyroid transcription factor-1 (Nkx2.1) regulate Abca3 gene expression." American Journal of Physiology-Lung Cellular and Molecular Physiology 293, no. 6 (2007): L1395—L1405. http://dx.doi.org/10.1152/ajplung.00275.2007.
Texte intégralRésumé :
The ATP-binding cassette (ABC) ABCA3 gene encodes a lipid transporter critical for surfactant function at birth. To identify transcription factors that regulate ABCA3 expression in the lung, we identified by bioinformatic and functional analyses two positive regulatory regions, located between bp −2591 and −1102 and bp −1102 and +11, relative to the exon 1 of the Abca3 gene promoter. The distal cassette contains consensus sequences predicting binding to lung transcription factors including FOXA2, CCAAT/enhancer binding protein-α (C/EBPα), GATA-6, thyroid transcription factor-1 (TTF-1 or Nkx2.1), and nuclear factor of activated T cells-c3 (NFATc3). The activity of the distal region from bp −2591 to −1102 was assessed in HeLa and mouse lung epithelial MLE-15 cells. FOXA2, C/EBPα, GATA-6, TTF-1, and NFATc3 increased the activity of the Abca3 luciferase construct in a dose-dependent manner. The distal cassette conferred activation by FOXA2, C/EBPα, GATA-6, TTF-1, and NFATc3 in a position- and orientation-independent manner, serving as an enhancer-like regulatory element. The proximal Abca3 promoter region contained multiple sterol responsive element (SRE) binding sites. SRE binding protein (SREBP)-1c significantly increased the activity of the Abca3 luciferase construct in a dose-dependent manner, whereas SREBP-1a and SREBP-2 did not influence the Abca3 promoter activity. Chromatin immunoprecipitation (ChIP) analyses demonstrated the binding of SREBP-1c, C/EBPα, and TTF-1 to their respective regulatory elements. Conditional deletion of SREBP cleavage-activating protein ( Scap) in respiratory epithelial cells in the mouse lung in vivo inhibited the expression of SREBPs in concert with Abca3. Abca3 gene expression is mediated by discrete cis-acting cassettes that mediate pulmonary cell- and lipid-sensitive pathways regulating surfactant homeostasis.
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Makabe, K. W., C. V. Kirchhamer, R. J. Britten, and E. H. Davidson. "Cis-regulatory control of the SM50 gene, an early marker of skeletogenic lineage specification in the sea urchin embryo." Development 121, no. 7 (1995): 1957–70. http://dx.doi.org/10.1242/dev.121.7.1957.
Texte intégralRésumé :
The SM50 gene encodes a minor matrix protein of the sea urchin embryo spicule. We carried out a detailed functional analysis of a cis-regulatory region of this gene, extending 440 bp upstream and 120 bp downstream of the transcription start site, that had been shown earlier to confer accurate skeletogenic expression of an injected expression vector. The distal portion of this fragment contains elements controlling amplitude of expression, while the region from −200 to +105 contains spatial control elements that position expression accurately in the skeletogenic lineages of the embryo. A systematic mutagenesis analysis of this region revealed four adjacent regulatory elements, viz two copies of a positively acting sequence (element D) that are positioned just upstream of the transcription start site; an indispensable spatial control element (element C) that is positioned downstream of the start site; and further downstream, a second positively acting sequence (element A). We then constructed a series of synthetic expression constructs. These contained oligonucleotides representing normal and mutated versions of elements D, C, and A, in various combinations. We also changed the promoter of the SM50 gene from a TATA-less to a canonical TATA box form, without any effect on function. Perfect spatial regulation was also produced by a final series of constructs that consisted entirely of heterologous enhancers from the CyIIIa gene, the SV40 early promoter, and synthetic D, C, and A elements. We demonstrate that element C exercises the primary spatial control function of the region we analyzed. We term this a ‘locator’ element. This differs from conventional ‘tissue-specific enhancers’ in that while it is essential for expression, it has no transcriptional activity on its own, and it requires other, separable, positive regulatory elements for activity. In the normal configuration these ancillary positive functions are mediated by elements A and D. Only positively acting control elements were observed in the SM50 regulatory domain throughout this analysis.
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Owen, Ashley N., Robert I. Liem, Andre M. Pilon, Patrick G. Gallagher, and David M. Bodine. "Chromatin Conformation and a Distal Regulatory Element Activate the Human Erythroid Ankyrin-1 Promoter." Blood 106, no. 11 (2005): 803. http://dx.doi.org/10.1182/blood.v106.11.803.803.
Texte intégralRésumé :
Abstract Ankyrin forms the bridge between the spectrin/actin network of the erythrocyte membrane skeleton and the red cell membrane by binding to both β-spectrin and band 3. The erythrocyte ankyrin promoter (Ank-1E) is active only in erythroid cells, while two other Ank-1 promoters located 20 kb downstream and 40 kb upstream of Ank-1E are active in the cerebellum and muscle cells respectively. We have been studying the mechanism by which the Ank-1E promoter becomes active in erythroid cells by studying the cis acting regulatory elements and the chromatin structure of the Ank-1 promoter region. We have previously shown that the sequences between −296 and −15 of the Ank-1E promoter are fully sufficient for erythroid specific, copy number dependent uniform expression of reporter genes in transgenic mice. We have also mapped a DNase I Hypersensitive site (5′HS) between −300 and −100 of the human and mouse Ank-1E promoters in human K562 and mouse fetal liver cells. Both the mouse and human 5′HS are capable of preventing the silencing of a β-globin/GFP reporter gene in K562 cells, establishing that they function as barrier elements. Consistent with this observation, the human and mouse 5′HS are hyperacetylated in erythroid cells. The chromatin 10 kb 5′ to the 5′HS is DNase I resistant (associated with inactive chromatin) in human and mouse erythroid and non-erythroid cells. Approximately 6 kb 3′ to 5′HS are two adjacent HS (3′HS1, 3′HS2). Beyond 3′HS2 the chromatin is also DNase I resistant in both human and mouse erythroid and non-erythroid cells. Between 5′HS and 3′HS1 the 6kb region is DNase I sensitive (active) in erythroid cells but not in other cell types. We hypothesized that this 6 kb region contains regulatory elements that activate the Ank-1E promoter. To screen for regulatory elements we isolated overlapping segments of a 10 kb region extending from 2 kb upstream of 5′HS to 2 kb downstream of 3′HS2. We inserted these fragments into a plasmid vector containing the Ank-1E promoter linked to a luciferase reporter gene and transfected these constructs into K562 cells. A single region up regulated Ank-1E/luciferase expression. This region mapped to a 211bp segment that included 3′HS1, but did not include 3′HS2. A fragment containing only 3′HS2 did not up regulate an Ank-1E/luciferase reporter gene, but 3′HS2 was capable of preventing the silencing of a β-globin/Green Fluorescent Protein reporter gene in K562 cells, demonstrating barrier activity. The region around 3′HS1 and 2 was also a site of histone hyperacetylation. The sequence of the 211 bp fragment containing 3′HS1 does not contain consensus sequences for any known erythroid-specific transcription factors, but does contain potential binding sites fro Sp1, AP-1 and E-box binding proteins. Using the Chromatin Conformation Capture assay we demonstrated that 5′HS and 3′HS1 and 2 are in close proximity in K562 chromatin, but are not closely associated in chromatin from other cell types. We propose that an erythroid-specific chromatin loop brings 3′HS1 and 2 into proximity with 5′HS, adjacent to the Ank-1E promoter. This interaction translocates the positive regulatory element in 3′HS1 to the Ank-1E promoter allowing the Ank-1E promoter to become active in erythroid cells.
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Westin, Gunnar, Jan Zabielski, Lars Janson, and Ulf Pettersson. "Properties of a distal regulatory element controlling transcription of the U2 small nuclear RNA." Gene 59, no. 2-3 (1987): 183–90. http://dx.doi.org/10.1016/0378-1119(87)90326-x.
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Glanville, David G., Ozcan Gazioglu, Michela Marra, et al. "Pneumococcal capsule expression is controlled through a conserved, distal cis-regulatory element during infection." PLOS Pathogens 19, no. 1 (2023): e1011035. http://dx.doi.org/10.1371/journal.ppat.1011035.
Texte intégralRésumé :
Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial pneumonia in the US and worldwide. Studies have shown that the differing chemical make-up between serotypes of its most important virulence factor, the capsule, can dictate disease severity. Here we demonstrate that control of capsule synthesis is also critical for infection and facilitated by two broadly conserved transcription factors, SpxR and CpsR, through a distal cis-regulatory element we name the 37-CE. Strikingly, changing only three nucleotides within this sequence is sufficient to render pneumococcus avirulent. Using in vivo and in vitro approaches, we present a model where SpxR interacts as a unique trimeric quaternary structure with the 37-CE to enable capsule repression in the airways. Considering its dramatic effect on infection, variation of the 37-CE between serotypes suggests this molecular switch could be a critical contributing factor to this pathogen’s serotype-specific disease outcomes.
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Yeom, Y. I., G. Fuhrmann, C. E. Ovitt, et al. "Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells." Development 122, no. 3 (1996): 881–94. http://dx.doi.org/10.1242/dev.122.3.881.
Texte intégralRésumé :
The totipotent stem cells of the pregastrulation mouse embryo which give rise to all embryonic somatic tissues and germ cells express Oct-4. The expression is downregulated during gastrulation and is thereafter only maintained in the germline lineage. Oct-4/lacZ transgenes were used to determine how this pattern of expression was achieved, and resulted in the identification of two separate regulatory elements. The distal element drives Oct-4 expression in preimplantation embryos, in migratory and postmigratory primordial germ cells but is inactive in cells of the epiblast. In cell lines this element is specifically active in embryonic stem and embryonic germ cells. The proximal element directs the epiblast-specific expression pattern, including downregulation during gastrulation; in cell lines its activity is restricted to epiblast-derived cells. Thus, Oct-4 expression in the germline is regulated separately from epiblast expression. This provides the first marker for the identification of totipotent cells in the embryo, and suggests that expression of Oct-4 in the totipotent cycle is dependent on a set of factors unique to the germline.
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Magee, Jeffrey A., Li-wei Chang, Gary D. Stormo, and Jeffrey Milbrandt. "Direct, Androgen Receptor-Mediated Regulation of the FKBP5 Gene via a Distal Enhancer Element." Endocrinology 147, no. 1 (2006): 590–98. http://dx.doi.org/10.1210/en.2005-1001.
Texte intégralRésumé :
Androgen signaling via the androgen receptor (AR) transcription factor is crucial to normal prostate homeostasis and prostate tumorigenesis. Current models of AR function are predominantly based on studies of prostate-specific antigen regulation in androgen-responsive cell lines. To expand on these in vitro paradigms, we used the mouse prostate to elucidate the mechanisms through which AR regulates another direct target, FKBP5, in vivo. FKBP5 encodes an immunophilin that has been previously implicated in glucocorticoid and progestin signaling pathways and that likely influences prostate physiology in the presence of androgens. In this work, we show that androgens directly regulate FKBP5 via an interaction between the AR and a distal enhancer located 65 kb downstream of the transcription start site in the fifth intron of the FKBP5 gene. We have found that AR selectively recruits cAMP response element-binding protein to this enhancer. These interactions, in turn, result in chromatin remodeling that affects the enhancer proper but not the FKBP5 locus as a whole. Furthermore, in contrast to prostate-specific antigen-regulatory mechanisms, we show that transactivation of the FKBP5 gene does not rely on a single looping complex to mediate communication between the distal enhancer and proximal promoter. Rather, the distal enhancer complex and basal transcription apparatus communicate indirectly with one another, implicating a regulatory mechanism that has not been previously appreciated for AR target genes.
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Griggs, D. W., and M. Johnston. "Promoter elements determining weak expression of the GAL4 regulatory gene of Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 8 (1993): 4999–5009. http://dx.doi.org/10.1128/mcb.13.8.4999-5009.1993.
Texte intégralRésumé :
The GAL4 gene of Saccharomyces cerevisiae (encoding the activator of transcription of the GAL genes) is poorly expressed and is repressed during growth on glucose. To determine the basis for its weak expression and to identify DNA sequences recognized by proteins that activate transcription of a gene that itself encodes an activator of transcription, we have analyzed GAL4 promoter structure. We show that the GAL4 promoter is about 90-fold weaker than the strong GAL1 promoter and at least 7-fold weaker than the feeble URA3 promoter and that this low level of GAL4 expression is primarily due to a weak promoter. By deletion mapping, the GAL4 promoter can be divided into three functional regions. Two of these regions contain positive elements; a distal region termed the UASGAL4 (upstream activation sequence) contains redundant elements that increase promoter function, and a central region termed the UESGAL4 (upstream essential sequence) is essential for even basal levels of GAL4 expression. The third element, an upstream repression sequence, mediates glucose repression of GAL4 expression and is located between the UES and the transcriptional start site. The UASGAL4 is unusual because it is not interchangable with UAS elements in other yeast promoters; it does not function as a UAS element when inserted in a CYC1 promoter, and a normally strong UAS functions poorly in place of UASGAL4 in the GAL4 promoter. Similarly, the UES element of GAL4 does not function as a TATA element in a test promoter, and consensus TATA elements do not function in place of UES elements in the GAL4 promoter. These results suggest that GAL4 contains a weak TATA-less promoter and that the proteins regulating expression of this regulatory gene may be novel and context specific.
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Griggs, D. W., and M. Johnston. "Promoter elements determining weak expression of the GAL4 regulatory gene of Saccharomyces cerevisiae." Molecular and Cellular Biology 13, no. 8 (1993): 4999–5009. http://dx.doi.org/10.1128/mcb.13.8.4999.
Texte intégralRésumé :
The GAL4 gene of Saccharomyces cerevisiae (encoding the activator of transcription of the GAL genes) is poorly expressed and is repressed during growth on glucose. To determine the basis for its weak expression and to identify DNA sequences recognized by proteins that activate transcription of a gene that itself encodes an activator of transcription, we have analyzed GAL4 promoter structure. We show that the GAL4 promoter is about 90-fold weaker than the strong GAL1 promoter and at least 7-fold weaker than the feeble URA3 promoter and that this low level of GAL4 expression is primarily due to a weak promoter. By deletion mapping, the GAL4 promoter can be divided into three functional regions. Two of these regions contain positive elements; a distal region termed the UASGAL4 (upstream activation sequence) contains redundant elements that increase promoter function, and a central region termed the UESGAL4 (upstream essential sequence) is essential for even basal levels of GAL4 expression. The third element, an upstream repression sequence, mediates glucose repression of GAL4 expression and is located between the UES and the transcriptional start site. The UASGAL4 is unusual because it is not interchangable with UAS elements in other yeast promoters; it does not function as a UAS element when inserted in a CYC1 promoter, and a normally strong UAS functions poorly in place of UASGAL4 in the GAL4 promoter. Similarly, the UES element of GAL4 does not function as a TATA element in a test promoter, and consensus TATA elements do not function in place of UES elements in the GAL4 promoter. These results suggest that GAL4 contains a weak TATA-less promoter and that the proteins regulating expression of this regulatory gene may be novel and context specific.
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Qasba, P., E. Lin, M. D. Zhou, A. Kumar, and M. A. Siddiqui. "A single transcription factor binds to two divergent sequence elements with a common function in cardiac myosin light chain-2 promoter." Molecular and Cellular Biology 12, no. 3 (1992): 1107–16. http://dx.doi.org/10.1128/mcb.12.3.1107-1116.1992.
Texte intégralRésumé :
The cardiac myosin light chain-2 (MLC-2) gene promoter contains several positive and negative cis-acting sequences that are involved in the regulation of its expression. We describe here the properties of two activator sequences, elements A and P, and their DNA-binding factors (ABFs). Element A (CCAAAAGTGG), located at -61, has homology with the evolutionarily conserved sequence CC(A/T)6GG, present in the genes of many contractile proteins. Element P (TAACCTTGAAAGC), located 114 bp upstream of element A, is conserved in both chicken and rat cardiac MLC-2 gene promoters. Deletion mutagenesis demonstrated that these two elements are involved in the positive regulation of MLC-2 gene transcription. At least two sequence-specific element A-binding proteins, ABF-1 and ABF-2, were identified by gel shift analysis of the fractionated cardiac nuclear proteins. ABF-1 binds to element A with strict dependence on the internal element A sequence AAAAGT. In contrast, ABF-2 exhibits a relaxed sequence requirement, as it recognizes the consensus CArG and CCAAT box sequences as well. ABF-2 also recognizes the distal element P despite the fact that the sequences of elements A and P are divergent. DNase I footprinting, methylation interference, and gel shift analyses demonstrated unequivocally that the element A-DNA affinity-purified protein ABF-2 binds to element P with sequence specificity. Since both elements A and P play a positive regulatory role in MLC-2 gene transcription and bind to a single protein (ABF-2), it would appear that ABF-2 is a key transcription factor with the ability to recognize divergent sequence elements involved in a common regulatory pathway during myogenesis.
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Qasba, P., E. Lin, M. D. Zhou, A. Kumar, and M. A. Siddiqui. "A single transcription factor binds to two divergent sequence elements with a common function in cardiac myosin light chain-2 promoter." Molecular and Cellular Biology 12, no. 3 (1992): 1107–16. http://dx.doi.org/10.1128/mcb.12.3.1107.
Texte intégralRésumé :
The cardiac myosin light chain-2 (MLC-2) gene promoter contains several positive and negative cis-acting sequences that are involved in the regulation of its expression. We describe here the properties of two activator sequences, elements A and P, and their DNA-binding factors (ABFs). Element A (CCAAAAGTGG), located at -61, has homology with the evolutionarily conserved sequence CC(A/T)6GG, present in the genes of many contractile proteins. Element P (TAACCTTGAAAGC), located 114 bp upstream of element A, is conserved in both chicken and rat cardiac MLC-2 gene promoters. Deletion mutagenesis demonstrated that these two elements are involved in the positive regulation of MLC-2 gene transcription. At least two sequence-specific element A-binding proteins, ABF-1 and ABF-2, were identified by gel shift analysis of the fractionated cardiac nuclear proteins. ABF-1 binds to element A with strict dependence on the internal element A sequence AAAAGT. In contrast, ABF-2 exhibits a relaxed sequence requirement, as it recognizes the consensus CArG and CCAAT box sequences as well. ABF-2 also recognizes the distal element P despite the fact that the sequences of elements A and P are divergent. DNase I footprinting, methylation interference, and gel shift analyses demonstrated unequivocally that the element A-DNA affinity-purified protein ABF-2 binds to element P with sequence specificity. Since both elements A and P play a positive regulatory role in MLC-2 gene transcription and bind to a single protein (ABF-2), it would appear that ABF-2 is a key transcription factor with the ability to recognize divergent sequence elements involved in a common regulatory pathway during myogenesis.
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Thompson, M. A., E. Lee, D. Lawe, E. Gizang-Ginsberg, and E. B. Ziff. "Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a negative regulatory element." Molecular and Cellular Biology 12, no. 6 (1992): 2501–13. http://dx.doi.org/10.1128/mcb.12.6.2501-2513.1992.
Texte intégralRésumé :
The peripherin gene, which encodes a neuronal-specific intermediate filament protein, is transcriptionally induced with a late time course when nerve growth factor (NGF) stimulates PC12 cells to differentiate into neurons. We have studied its transcriptional regulation in order to better understand the neuronal-specific end steps of the signal transduction pathway of NGF. By 5' deletion mapping of the peripherin promoter, we have localized two positive regulatory elements necessary for full induction by NGF: a distal positive element and a proximal constitutive element within 111 bp of the transcriptional start site. In addition, there is a negative regulatory element (NRE; -179 to -111), the deletion of which results in elevated basal expression of the gene. Methylation interference footprinting of the NRE defined a unique sequence, GGCAGGGCGCC, as the binding site for proteins present in nuclear extracts from both undifferentiated and differentiated PC12 cells. However, DNA mobility shift assays using an oligonucleotide probe containing the footprinted sequence demonstrate a prominent retarded complex in extracts from undifferentiated PC12 cells which migrates with slower mobility than do the complexes produced by using differentiated PC12 cell extract. Transfection experiments using peripherin-chloramphenicol acetyltransferase constructs in which the footprinted sequence has been mutated confirm that the NRE has a functional, though not exclusive, role in repressing peripherin expression in undifferentiated and nonneuronal cells. We propose a two-step model of activation of peripherin by NGF in which dissociation of a repressor from the protein complex at the NRE, coupled with a positive signal from the distal positive element, results in depression of the gene.
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Thompson, M. A., E. Lee, D. Lawe, E. Gizang-Ginsberg, and E. B. Ziff. "Nerve growth factor-induced derepression of peripherin gene expression is associated with alterations in proteins binding to a negative regulatory element." Molecular and Cellular Biology 12, no. 6 (1992): 2501–13. http://dx.doi.org/10.1128/mcb.12.6.2501.
Texte intégralRésumé :
The peripherin gene, which encodes a neuronal-specific intermediate filament protein, is transcriptionally induced with a late time course when nerve growth factor (NGF) stimulates PC12 cells to differentiate into neurons. We have studied its transcriptional regulation in order to better understand the neuronal-specific end steps of the signal transduction pathway of NGF. By 5' deletion mapping of the peripherin promoter, we have localized two positive regulatory elements necessary for full induction by NGF: a distal positive element and a proximal constitutive element within 111 bp of the transcriptional start site. In addition, there is a negative regulatory element (NRE; -179 to -111), the deletion of which results in elevated basal expression of the gene. Methylation interference footprinting of the NRE defined a unique sequence, GGCAGGGCGCC, as the binding site for proteins present in nuclear extracts from both undifferentiated and differentiated PC12 cells. However, DNA mobility shift assays using an oligonucleotide probe containing the footprinted sequence demonstrate a prominent retarded complex in extracts from undifferentiated PC12 cells which migrates with slower mobility than do the complexes produced by using differentiated PC12 cell extract. Transfection experiments using peripherin-chloramphenicol acetyltransferase constructs in which the footprinted sequence has been mutated confirm that the NRE has a functional, though not exclusive, role in repressing peripherin expression in undifferentiated and nonneuronal cells. We propose a two-step model of activation of peripherin by NGF in which dissociation of a repressor from the protein complex at the NRE, coupled with a positive signal from the distal positive element, results in depression of the gene.
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Xiang, M., S. Y. Lu, M. Musso, G. Karsenty, and W. H. Klein. "A G-string positive cis-regulatory element in the LpS1 promoter binds two distinct nuclear factors distributed non-uniformly in Lytechinus pictus embryos." Development 113, no. 4 (1991): 1345–55. http://dx.doi.org/10.1242/dev.113.4.1345.
Texte intégralRésumé :
The LpS1 alpha and beta genes of Lytechinus pictus are activated at the late cleavage stage of embryogenesis, with LpS1 mRNAs accumulating only in lineages contributing to aboral ectoderm. We had shown previously that 762 bp of 5' flanking DNA from the LpS1 beta gene was sufficient for proper temporal and aboral ectoderm specific expression. In the present study, we identified a strong positive cis-regulatory element at −70 bp to −75 bp in the LpS1 beta promoter with the sequence (G)6 and a similar, more distal cis-element at −721 bp to −726 bp. The proximal ‘G-string’ element interacted with two nuclear factors, one specific to ectoderm and one to endoderm/mesoderm nuclear extracts, whereas the distal G-string element interacted only with the ectoderm factor. The ectoderm and endoderm/mesoderm G-string factors were distinct based on their migratory behavior in electrophoretic mobility shift assays, binding site specificities, salt optima and EDTA sensitivity. The proximal G-string element shared homology with a binding site for the mammalian transcription factor IF1, a protein that binds to negative cis-regulatory elements in the mouse alpha 1(I) and alpha 2(I) collagen gene promoters. Competition experiments using wild-type and mutant oligonucleotides indicated that the ectoderm G-string factor and IF1 have similar recognition sites. Partially purified IF1 specifically bound to an oligonucleotide containing the proximal G-string of LpS1 beta. From our results, we suggest that the ectoderm G-string factor, a member of the G-rich DNA-binding protein family, activates the LpS1 gene in aboral ectoderm cells by binding to the LpS1 promoter at the proximal G-string site.
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Goubert, Clément, Nicolas Arce Zevallos, and Cédric Feschotte. "Contribution of unfixed transposable element insertions to human regulatory variation." Philosophical Transactions of the Royal Society B: Biological Sciences 375, no. 1795 (2020): 20190331. http://dx.doi.org/10.1098/rstb.2019.0331.
Texte intégralRésumé :
Thousands of unfixed transposable element (TE) insertions segregate in the human population, but little is known about their impact on genome function. Recently, a few studies associated unfixed TE insertions to mRNA levels of adjacent genes, but the biological significance of these associations, their replicability across cell types and the mechanisms by which they may regulate genes remain largely unknown. Here, we performed a TE-expression QTL analysis of 444 lymphoblastoid cell lines (LCL) and 289 induced pluripotent stem cells using a newly developed set of genotypes for 2743 polymorphic TE insertions. We identified 211 and 176 TE-eQTL acting in cis in each respective cell type. Approximately 18% were shared across cell types with strongly correlated effects. Furthermore, analysis of chromatin accessibility QTL in a subset of the LCL suggests that unfixed TEs often modulate the activity of enhancers and other distal regulatory DNA elements, which tend to lose accessibility when a TE inserts within them. We also document a case of an unfixed TE likely influencing gene expression at the post-transcriptional level. Our study points to broad and diverse cis -regulatory effects of unfixed TEs in the human population and underscores their plausible contribution to phenotypic variation. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
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Kerschner, Jenny L., and Ann Harris. "Transcriptional networks driving enhancer function in the CFTR gene." Biochemical Journal 446, no. 2 (2012): 203–12. http://dx.doi.org/10.1042/bj20120693.
Texte intégralRésumé :
A critical cis-regulatory element for the CFTR (cystic fibrosis transmembrane conductance regulator) gene is located in intron 11, 100 kb distal to the promoter, with which it interacts. This sequence contains an intestine-selective enhancer and associates with enhancer signature proteins, such as p300, in addition to tissue-specific TFs (transcription factors). In the present study we identify critical TFs that are recruited to this element and demonstrate their importance in regulating CFTR expression. In vitro DNase I footprinting and EMSAs (electrophoretic mobility-shift assays) identified four cell-type-selective regions that bound TFs in vitro. ChIP (chromatin immunoprecipitation) identified FOXA1/A2 (forkhead box A1/A2), HNF1 (hepatocyte nuclear factor 1) and CDX2 (caudal-type homeobox 2) as in vivo trans-interacting factors. Mutation of their binding sites in the intron 11 core compromised its enhancer activity when measured by reporter gene assay. Moreover, siRNA (small interfering RNA)-mediated knockdown of CDX2 caused a significant reduction in endogenous CFTR transcription in intestinal cells, suggesting that this factor is critical for the maintenance of high levels of CFTR expression in these cells. The ChIP data also demonstrate that these TFs interact with multiple cis-regulatory elements across the CFTR locus, implicating a more global role in intestinal expression of the gene.
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Wöhner, Miriam, Hiromi Tagoh, Ivan Bilic, et al. "Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development." Journal of Experimental Medicine 213, no. 7 (2016): 1201–21. http://dx.doi.org/10.1084/jem.20152002.
Texte intégralRésumé :
E2A is an essential regulator of early B cell development. Here, we have demonstrated that E2A together with E2-2 controlled germinal center (GC) B cell and plasma cell development. As shown by the identification of regulated E2A,E2-2 target genes in activated B cells, these E-proteins directly activated genes with important functions in GC B cells and plasma cells by inducing and maintaining DNase I hypersensitive sites. Through binding to multiple enhancers in the Igh 3′ regulatory region and Aicda locus, E-proteins regulated class switch recombination by inducing both Igh germline transcription and AID expression. By regulating 3′ Igk and Igh enhancers and a distal element at the Prdm1 (Blimp1) locus, E-proteins contributed to Igk, Igh, and Prdm1 activation in plasmablasts. Together, these data identified E2A and E2-2 as central regulators of B cell immunity.
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Schott, D. R., P. D. East, and K. Paigen. "Characterization of the AdhSL regulatory mutation in Drosophila melanogaster." Genetics 119, no. 3 (1988): 631–37. http://dx.doi.org/10.1093/genetics/119.3.631.
Texte intégralRésumé :
Abstract We describe the characterization of a previously reported control mutation, AdhSL, in the alcohol dehydrogenase gene of Drosophila melanogaster, which results in decreased production of ADH molecules and subsequently lower ADH activity in adults. We find that the regulatory element modifies ADH mRNA levels and acts cis on both ADH protein and mRNA. It is not promoter specific but is developmentally specific to the adult stage. The AdhSL allele carries a 4.5-kb insert approximately 3 kb 5' to the distal promoter. This new insertion may be responsible for the regulatory phenotype of AdhSL.
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BANKS, Eric B., James F. CRISH, Jean F. WELTER, and Richard L. ECKERT. "Characterization of human involucrin promoter distal regulatory region transcriptional activator elements–a role for Sp1 and AP1 binding sites." Biochemical Journal 331, no. 1 (1998): 61–68. http://dx.doi.org/10.1042/bj3310061.
Texte intégralRésumé :
Human involucrin (hINV) is an important precursor of the keratinocyte cornified envelope that is specifically expressed in the suprabasal layers of stratifying epithelia. Previous truncation and mutagenesis experiments have shown that an activator protein 1 (Ap1) site, AP1–5, located 2100 bp upstream of the transcription start site, is required for optimal promoter activity. These previous studies suggest that AP1–5 is part of a distal regulatory region spanning nucleotides -2473 to -2088. In the present report, we study the distal regulatory region (DRR), which surrounds AP1–5. Our studies show that this region contains weak and strong activator elements spanning nucleotides -2473/-2216 and -2140/-2088, respectively. The strong activator element contains AP1–5 and an adjacent specificity protein 1 (Sp1) site. The AP1–5 site is absolutely required for DRR activity, as its mutation reduces transcription to basal levels. Mutagenesis studies of the AP1–5 and Sp1 sites in the presence or absence of the weak activator element indicate that the Sp1 site and the weak activator element synergistically activate the AP1–5 site-dependent transcription. The cooperation between the Sp1 and AP1–5 sites is also observed in the context of the full-length promoter. Gel mobility shift and supershift studies show that Sp1, but not Sp2, Sp3 or Sp4 binds to the Sp1 site. When the Sp1 site is mutated or the distance between the AP1–5 and Sp1 site is increased, the binding of AP1 factors to AP1–5 is markedly reduced. Surprisingly, gel shift studies suggest that activation does not require the formation of a stable AP1/Sp1/DNA ternary complex. These studies suggest that the AP1–5 site is absolutely required for transcriptional activation, that the weak activator element and Sp1 sites serve to enhance this activation, and that the Sp1 site is required for optimal AP1 factor binding at the AP1–5 site.
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Levantini, Elena, Sanghoon Lee, Hanna S. Radomska, et al. "RUNX1 regulates theCD34gene in haematopoietic stem cells by mediating interactions with a distal regulatory element." EMBO Journal 30, no. 19 (2011): 4059–70. http://dx.doi.org/10.1038/emboj.2011.285.
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Jones, Daniel R., and Michael Leffak. "A Bifunctional Regulatory Element of the Human ApoA-I Gene Responsive to a Distal Enhancer." DNA and Cell Biology 18, no. 2 (1999): 107–19. http://dx.doi.org/10.1089/104454999315493.
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