Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Skala, Henriette; Porteu, Arlette; Thomas, Mélanie; Szajnert, Marie-France; Okazawa, Hitoshi; Kahn, Axel; Phan-Dinh-Tuy, Françoise

doi:10.1074/jbc.273.48.31806

Cited by 15 publications

(30 citation statements)

References 66 publications

(90 reference statements)

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“…In this paper, we first show that the distal and proximal regulatory sequences are also able to ensure the activation of the ubiquitous thymidine kinase (tk) 1 promoter specifically in the brain of transgenic mice. We also report that, in addition to the POU/WH motifs, these regions contain two strong in vitro binding sites for a brain-specific, thermostable protein, one located in the 0.6-kb proximal fragment and the other in the distal activating region.…”

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confidence: 99%

Novel Target Sequences for Pax-6 in the Brain-specific Activating Regions of the Rat Aldolase C Gene

Skala-Rubinson

Vinh²,

Labas³

et al. 2002

Journal of Biological Chemistry

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Upstream activating sequences of the rat aldolase C gene are shown here to confer brain-specific expression in transgenic mice. In addition to binding sites described previously for the brain-expressed POU proteins Brn-1 and Brn-2 (Skala, H., Porteu, A., Thomas, M., Szajnert, M. F., Okazawa, H., Kahn, A., and Phan-DinhTuy, F. (1998) J. Biol. Chem. 273, 31806 -31814), we have identified two novel DNA elements critical for an interaction with a brain-specific, high affinity DNA-binding protein. Characterization of this binding protein showed it to be sensitive to thiol oxidation and stable to heat at 100°C. This protein was purified on the basis of its thermostability and its selective adsorption to streptavidin magnetic particles via a biotinylated multimer of its target DNA binding site. Liquid chromatography coupled to tandem mass spectrometry analysis, binding competition with consensus oligonucleotides, and antibody supershift assays led to its identification as the homeodomain paired protein Pax-6. This result suggests that the brain-specific aldolase C gene could constitute a new target for the transcription factor Pax-6, which is implicated increasingly in neurogenesis.Regulation of gene transcription in active chromatin is dependent upon the interaction of discrete DNA motifs with regulatory proteins. These proteins either represent basal, ubiquitous elements of the transcriptional machinery or can be themselves expressed in a tissue-, development-, or stimulusspecific manner. Cell-type diversity in the different organs can be considered as the result of multiple DNA-protein and protein-protein interactions leading to the controlled expression of a very large number of genes. The central nervous system is one of the most complex structures and consequently the one for which such regulatory mechanisms are probably still the least elucidated. In light of this, identification of DNA binding sites for transcription factors involved in brain development will help to define their candidate target genes and to elucidate the complex gene regulatory network at play in the central nervous system. The aldolase C gene encodes a brain-specific glycolytic enzyme, the fructose-1,6 diphosphate aldolase (EC 4.1.2.13). In a previous paper (1), we reported that the transcriptional activation of the brain-specific promoter (115 bp) of the rat aldolase C gene in vivo requires a cooperation between distal and proximal upstream sequences. We identified in vitro in a 0.6-kb proximal activating fragment several POU/WH motifs (1) exhibiting overlapping binding sites for the brain-restricted class III Brn-1 and Brn-2 POU proteins (2) and for the protein HNF3␤, a member of the WH (winged helix) factor family, which has been shown to be involved in the early brain development (3, 4).In this paper, we first show that the distal and proximal regulatory sequences are also able to ensure the activation of the ubiquitous thymidine kinase (tk) 1 promoter specifically in the brain of transgenic mice. We also report that, in addition to the ...

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confidence: 99%

Novel Target Sequences for Pax-6 in the Brain-specific Activating Regions of the Rat Aldolase C Gene

Skala-Rubinson

Vinh²,

Labas³

et al. 2002

Journal of Biological Chemistry

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“…This fragment is much shorter than the rat 6000-and 5500-bp promoter sequences used by Arai et al [10] and by Skala et al [12], respectively. Therefore, we have narrowed-down the region within which to search for the cis-element responsible for high aldolase C expression and its localization in hippocampal CA3 neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Notwithstanding numerous studies focusing on aldolase C in mammals [10][11][12]29], the human gene promoter region governing brain-and cell-specific aldolase C expression is not known. Our study conducted with three transgenic mice carrying the complete promoter region and a short and a long deletion in the distal promoter region, respectively, shows that diverse human aldolase C gene promoter regions are required to direct specific LacZ expression in different brain areas of these animals.…”

Section: Discussionmentioning

confidence: 99%

“…In the rat gene, the AT-rich sequences in the fragment located À800 bp from the transcription start site bind POU proteins [12,13]. It has been suggested that the binding of these proteins to the rat promoter gene results in brain-specific cis-acting elements that direct the neuronal expression of this gene [12]. Hence, it is not inconceivable that the aldolase C expression in CA3 hippocampal neurons in man observed in our study may be driven by a modular structure constituted by an AT-rich motif in the human promoter distal region and cis-acting elements in the promoter proximal region.…”

Section: Discussionmentioning

confidence: 99%

“…Aldolase C gene expression has been investigated in both in vivo and in vitro models. The proximal region of the rat promoter, spanning about 115 bp upstream from the major transcriptional start site, is able to direct CAT-reporter gene expression, albeit at low levels, in the brain of transgenic mice [10][11][12]. The upstream region binds Pax-6 transcriptional factor and is involved in the activation of rat aldolase C gene expression in the brain of transgenic mice [13].…”

Section: Introductionmentioning

confidence: 99%

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Diverse human aldolase C gene promoter regions are required to direct specific LacZ expression in the hippocampus and Purkinje cells of transgenic mice

et al. 2004

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Aldolase C is selectively expressed in the hippocampus and Purkinje cells in adult mammalian brain. The gene promoter regions governing cell-specific aldolase C expression are obscure. We show that aldolase C messenger expression in the hippocampus is restricted to CA3 neurons. The human distal promoter region (À200/À1200 bp) is essential for b-galactosidase (b-gal) expression in CA3 neurons and drives high stripe-like b-gal expression in Purkinje cells. The 200 bp proximal promoter region is sufficient to drive low brain-specific and stripe-like b-gal expression in Purkinje cells. Thus, the human aldolase C gene sequences studied drive endogenous-like expression in the brain.

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Cell Specificity of the Transcription-Factor Repertoire Used by a Lentivirus: Motifs Important for Expression of Equine Infectious Anemia Virus in Nonmonocytic Cells

et al. 2000

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The equine infectious anemia virus (EIAV) long-terminal repeat (LTR) has been identified as highly variable, both in infected horses and in cell culture. This nucleotide hypervariation is localized to the LTR enhancer region. The EIAV LTR has been implicated in controlling both the cell tropism and virulence of the virus and it is postulated that the enhancer-region hypervariation may be responsible for the LTR effects. Our previous studies have demonstrated that the presence of DNA motifs bound by the ets transcription-factor family member PU.1 are critically important for EIAV expression in equine macrophages. Here we identify and characterize the EIAV LTR enhancer motifs PEA-2, Lvb, Oct, and CRE, that bind to fibroblast nuclear extracts. Three of these four motifs, PEA-2, Oct, and CRE, were determined to be important for expression of the LTR in a fibroblast cell line that supports productive infection of EIAV. These motifs that are important for expression of the LTR in fibroblasts were found to be interdigitated between the PU.1 sites. We hypothesize that the combination of motif interdigitation and cell-specific usage of these motifs may be responsible for the observed EIAV LTR enhancer-region hypervariation.

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Upstream Elements Involved in Vivo in Activation of the Brain-specific Rat Aldolase C Gene

Cited by 15 publications

References 66 publications

Novel Target Sequences for Pax-6 in the Brain-specific Activating Regions of the Rat Aldolase C Gene

Novel Target Sequences for Pax-6 in the Brain-specific Activating Regions of the Rat Aldolase C Gene

Diverse human aldolase C gene promoter regions are required to direct specific LacZ expression in the hippocampus and Purkinje cells of transgenic mice

Cell Specificity of the Transcription-Factor Repertoire Used by a Lentivirus: Motifs Important for Expression of Equine Infectious Anemia Virus in Nonmonocytic Cells

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