ALU Repeats in Promoters Are Position-Dependent Co-Response Elements (coRE) that Enhance or Repress Transcription by Dimeric and Monomeric Progesterone Receptors

Jacobsen, Britta M.; Jambal, Purevsuren; Schittone, Stephanie A.; Horwitz, Kathryn B.

doi:10.1210/me.2009-0048

Cited by 40 publications

(48 citation statements)

References 68 publications

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“…Moreover, during these investigations, a possibility that the PR might also have a subset of PR-selective PREs became apparent. This was also suggested in a recent paper by Jacobsen et al (31). During the finalization of this manuscript, Jiang et al (40) described an androgen-responsive gene database.…”

Section: Evaluation Of Pspmsupporting

confidence: 57%

The Rules of DNA Recognition by the Androgen Receptor

Denayer

Helsen

Thorrez³

et al. 2010

Molecular Endocrinology

125

126

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The androgen receptor (AR) and glucocorticoid, progestagen, and mineralocorticoid receptors all recognize classical DNA response elements that are organized as inverted repeats of 5'-AGAACA-3'-like motifs with a three-nucleotide spacer. Next to such elements, the AR also recognizes a second type of androgen response element (ARE), the so-called selective AREs, which resemble more the direct repeats of the same hexamer. In this work, we show that not only the AR but also the progestagen receptor can recognize the selective AREs, whereas neither glucocorticoid nor mineralocorticoid receptor can. Recently, genomic AR-binding fragments have been postulated to contain AR-binding sites that diverge considerably from the classical ARE consensus. Extensive mutational analyses of these candidate motifs, however, reinstalls the values of the consensus sequence for the AREs as mentioned above, the importance of their dimeric nature and the presence of exactly three-nucleotide spacing. We developed a position-specific probability matrix that was used to predict with higher accuracy new AREs in different AR-binding regions. So far, all AR-binding genomic fragments that were analyzed contain AREs defined as receptor-dimer binding motifs with the ability to confer responsiveness to a reporter gene.

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Section: Evaluation Of Pspmsupporting

confidence: 57%

The Rules of DNA Recognition by the Androgen Receptor

Denayer

Helsen

Thorrez³

et al. 2010

Molecular Endocrinology

125

126

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“…Although this model has not been proven for polymorphic Alu elements, it is supported for evolutionarily older elements that are fixed in the genome, including Alu elements that act as tissue-specific enhancers (e.g., refs. 71,72). Fixed Alu can also provide alternatively used exons (e.g., refs.…”

Section: Discussionmentioning

confidence: 99%

Structural variants caused byAluinsertions are associated with risks for many human diseases

Payer

Steranka

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

126

102

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Interspersed repeat sequences comprise much of our DNA, although their functional effects are poorly understood. The most commonly occurring repeat is the Alu short interspersed element. New Alu insertions occur in human populations, and have been responsible for several instances of genetic disease. In this study, we sought to determine if there are instances of polymorphic Alu insertion variants that function in a common variant, common disease paradigm. We cataloged 809 polymorphic Alu elements mapping to 1,159 loci implicated in disease risk by genome-wide association study (GWAS) (P < 10−8). We found that Alu insertion variants occur disproportionately at GWAS loci (P = 0.013). Moreover, we identified 44 of these Alu elements in linkage disequilibrium (r2 > 0.7) with the trait-associated SNP. This figure represents a >20-fold increase in the number of polymorphic Alu elements associated with human phenotypes. This work provides a broader perspective on how structural variants in repetitive DNAs may contribute to human disease.

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“…In contrast to this, we found that the AR antagonist activity displayed by CpdA on a GRE-containing synthetic reporter in COS-1 cells was mimicked in BWTG3 cells for expressed AR-mediated regulation of endogenous TAT activity. It has been suggested that the flanking sequences around GREs may play an important role in receptor specificity (61) and that individual GREs retain specific "architectural signatures" that includes distinct GRbinding sites as well as binding motifs for other transcription factors (62). Thus by investigating only isolated transcription binding sites the role of these flanking sequences that may contribute to the composite elements (63) enriched for motives to GR as well as other transcription factors may be overlooked.…”

Section: Discussionmentioning

confidence: 99%

Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A

Robertson

Allie-Reid

Berghe

et al. 2010

Journal of Biological Chemistry

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Compound A (CpdA), a dissociated glucocorticoid receptor modulator, decreases corticosteroid-binding globulin (CBG), adrenocorticotropic hormone (ACTH), and luteneinizing hormone levels in rats. Whether this is due to transcriptional regulation by CpdA is not known. Using promoter reporter assays we show that CpdA, like dexamethasone (Dex), directly transrepresses these genes. Results using a rat Cbg proximal-promoter reporter construct in BWTG3 and HepG2 cell lines support a glucocorticoid receptor (GR)-dependent transrepression mechanism for CpdA. However, CpdA, unlike Dex, does not result in transactivation via glucocorticoid-responsive elements within a promoter reporter construct even when GR is co-transfected. The inability of CpdA to result in transactivation via glucocorticoid-responsive elements is confirmed on the endogenous tyrosine aminotransferase gene, whereas transrepression ability is confirmed on the endogenous CBG gene. Consistent with a role for CpdA in modulating GR activity, whole cell binding assays revealed that CpdA binds reversibly to the GR, but with lower affinity than Dex, and influences association of [ 3 H]Dex, but has no effect on dissociation. In addition, like Dex, CpdA causes nuclear translocation of the GR, albeit to a lesser degree. Several lines of evidence, including fluorescence resonance energy transfer, co-immunoprecipitation, and nuclear immunofluorescence studies of nuclear localization-deficient GR show that CpdA, unlike Dex, does not elicit ligand-induced GR dimerization. Comparison of the behavior of CpdA in the presence of wild type GR to that of Dex with a dimerization-deficient GR mutant (GR dim ) strongly supports the conclusion that loss of dimerization is responsible for the dissociated behavior of CpdA.

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ALU Repeats in Promoters Are Position-Dependent Co-Response Elements (coRE) that Enhance or Repress Transcription by Dimeric and Monomeric Progesterone Receptors

Cited by 40 publications

References 68 publications

The Rules of DNA Recognition by the Androgen Receptor

The Rules of DNA Recognition by the Androgen Receptor

Structural variants caused byAluinsertions are associated with risks for many human diseases

Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A

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