The assessment of noncoding variant of PPOX gene in variegate porphyria reveals post-transcriptional role of the 5′ untranslated exon 1

2016 ◽  
Vol 61 ◽  
pp. 48-53 ◽  
Author(s):  
Valeria Fiorentino ◽  
Valentina Brancaleoni ◽  
Francesca Granata ◽  
Giovanna Graziadei ◽  
Elena Di Pierro
Keyword(s):  
Variegate Porphyria ◽  
Untranslated Exon ◽  
Exon 1 ◽  
Noncoding Variant

scholarly journals Ikaros Is Regulated through Multiple Histone Modifications and Deoxyribonucleic Acid Methylation in the Pituitary

2007 ◽  
Vol 21 (5) ◽  
pp. 1205-1215 ◽  
Author(s):  
Xuegong Zhu ◽  
Sylvia L. Asa ◽  
Shereen Ezzat
Keyword(s):  
Dna Methylation ◽  
Histone Modifications ◽  
Cpg Island ◽  
Chromatin Accessibility ◽  
Dominant Negative ◽  
Nurd Complex ◽  
Human Pituitary ◽  
Untranslated Exon ◽  
Exon 1 ◽  
Mouse Pituitary

Abstract The transcription factor Ikaros (Ik) is at the center of a functionally diverse chromatin-remodeling network that is critical for the development and regulation of both the immune and endocrine systems. Dominant negative forms of Ik result in neoplastic growth in mouse genetic studies and have been identified in human tumors. Ik modulates chromatin accessibility through associations with members of the NURD complex including histone deacetylase complexes. We show here that Ik expression in mouse pituitary corticotroph cells is itself regulated through histone modifications as well as DNA methylation. Examination of primary human pituitary specimens also identified a correlation of loss of Ik expression with the presence of DNA methylation in the untranslated exon 1 CpG island. These findings have important implications for the understanding of Ikaros’ role in epigenetic functions and suggest a potential role for demethylating agents in the treatment of related disorders.

scholarly journals Non-Cell Autonomous and Epigenetic Mechanisms of Huntington’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12499
Author(s):  
Chaebin Kim ◽  
Ali Yousefian-Jazi ◽  
Seung-Hye Choi ◽  
Inyoung Chang ◽  
Junghee Lee ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Involuntary Movement ◽  
Therapeutic Approaches ◽  
Exon 1 ◽  
Human Chromosome 4 ◽  
The Brain

Huntington’s disease (HD) is a rare neurodegenerative disorder caused by an expansion of CAG trinucleotide repeat located in the exon 1 of Huntingtin (HTT) gene in human chromosome 4. The HTT protein is ubiquitously expressed in the brain. Specifically, mutant HTT (mHTT) protein-mediated toxicity leads to a dramatic degeneration of the striatum among many regions of the brain. HD symptoms exhibit a major involuntary movement followed by cognitive and psychiatric dysfunctions. In this review, we address the conventional role of wild type HTT (wtHTT) and how mHTT protein disrupts the function of medium spiny neurons (MSNs). We also discuss how mHTT modulates epigenetic modifications and transcriptional pathways in MSNs. In addition, we define how non-cell autonomous pathways lead to damage and death of MSNs under HD pathological conditions. Lastly, we overview therapeutic approaches for HD. Together, understanding of precise neuropathological mechanisms of HD may improve therapeutic approaches to treat the onset and progression of HD.

scholarly journals Androgen receptor gene CAG and GGC repeat lengths in cryptorchidism

2005 ◽  
Vol 152 (3) ◽  
pp. 419-425 ◽  
Author(s):  
Alberto Ferlin ◽  
Andrea Garolla ◽  
Andrea Bettella ◽  
Lucia Bartoloni ◽  
Cinzia Vinanzi ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Receptor Gene ◽  
Causative Factor ◽  
Androgen Receptor Gene ◽  
Cag Repeats ◽  
Exon 1 ◽  
History Of ◽  
Receptor Gene Polymorphisms ◽  
Congenital Birth Defect

Objective: Cryptorchidism is the most common congenital birth defect in male children, and accumulating evidence suggests that genetic abnormalities may be associated with it. The androgen receptor has two polymorphic sites in exon 1, with different numbers of CAG and GGC repeats, resulting in variable lengths of polyglutamine and polyglycine stretches. Longer CAG repeats result in a reduced androgen receptor transcriptional activity, but the role of the GGC triplets is less clear. In this study we analysed CAG and GGC repeat lengths in men with a history of cryptorchidism, associated or not with impairment of sperm production, in comparison with normal fertile subjects. Methods: We analysed CAG and GGC repeat lengths in a group of 105 ex-cryptorchid men in comparison with 115 fertile non-cryptorchid men. Results: No difference was found between patients and controls in the mean and median values, and in distribution of CAG and GGC, when considered separately. However, the analysis of the joint distribution of CAG and GGC showed that some combinations are significantly more frequent in men with bilateral cryptorchidism (who frequently presented severe testiculopathies), in a manner similar to that found in idiopathic infertile subjects. Conclusions: Although further studies are needed to elucidate the possible role of specific CAG/GGC combinations as a causative factor, these data suggest a possible association between androgen receptor gene polymorphisms and cryptorchidism.

Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 74-74
Author(s):  
Yoshiaki Yamamoto ◽  
Yohann Loriot ◽  
Eliana Beraldi ◽  
Tianyuan Zhou ◽  
Youngsoo Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Androgen Receptor ◽  
Cell Growth ◽  
Functional Role ◽  
Full Length ◽  
Lncap Cells ◽  
Exon 1

74 Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.

scholarly journals Functional Cooperation between Multiple Regulatory Elements in the Untranslated Exon 1 Stimulates the Basal Transcription of the Human GnRH-II Gene

2003 ◽  
Vol 17 (7) ◽  
pp. 1175-1191 ◽  
Author(s):  
Chi Keung Cheng ◽  
Ruby L. C. Hoo ◽  
Billy K. C. Chow ◽  
Peter C. K. Leung
Keyword(s):  
Gene Transcription ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Mutational Analysis ◽  
Regulatory Elements ◽  
Start Codon ◽  
Basal Transcription ◽  
Untranslated Exon ◽  
E Box ◽  
Exon 1

Abstract The wide distribution of GnRH-II and conservation of its structure over all vertebrate classes suggest that the neuropeptide possesses vital biological functions. Although recent studies have shown that the expression of the human GnRH-II gene is regulated by cAMP and estrogen, the molecular mechanisms governing its basal transcription remain poorly understood. Using the neuronal TE-671 and placental JEG-3 cells, we showed that the minimal human GnRH-II promoter was located between nucleotide −1124 and −750 (relative to the translation start codon) and that the untranslated exon 1 was important to produce full promoter activity. Two putative E-box binding sites and one Ets-like element were identified within the first exon, and mutational analysis demonstrated that these cis-acting elements functioned cooperatively to stimulate the human GnRH-II gene transcription. EMSAs, UV cross-linking, and Southwestern blot analyses indicated that the basic helix-loop-helix transcription factor AP-4 bound specifically to the two E-box binding sites, whereas an unidentified protein bound to the Ets-like element. The functional importance of AP-4 in controlling human GnRH-II gene transcription was demonstrated by overexpression of sense and antisense full-length AP-4 cDNAs. Taken together, our present data demonstrate a novel mechanism in stimulating basal human GnRH-II gene transcription mediated by cooperative actions of multiple regulatory elements within the untranslated first exon of the gene.

scholarly journals Targeted ablation of the PTH/PTHrP receptor in osteocytes impairs bone structure and homeostatic calcemic responses

2011 ◽  
Vol 209 (1) ◽  
pp. 21-32 ◽  
Author(s):  
William F Powell ◽  
Kevin J Barry ◽  
Irena Tulum ◽  
Tatsuya Kobayashi ◽  
Stephen E Harris ◽  
...  
Keyword(s):  
Volume Fraction ◽  
Bone Structure ◽  
Micro Computed Tomography ◽  
Bone Volume Fraction ◽  
Blood Calcium ◽  
Low Calcium Diet ◽  
Exon 1 ◽  
Skeletal Homeostasis ◽  
Pthrp Receptor

Parathyroid hormone (PTH) is a major physiologic regulator of calcium, phosphorous, and skeletal homeostasis. Cells of the osteoblastic lineage are key targets of PTH action in bone, and recent evidence suggests that osteocytes might be important in the anabolic effects of PTH. To understand the role of PTH signaling through the PTH/PTHrP receptors (PPR) in osteocytes and to determine the role(s) of these cells in mediating the effects of the hormone, we have generated mice in which PPR expression is specifically ablated in osteocytes. Transgenic mice in which the 10 kb-Dmp1 promoter drives a tamoxifen-inducible Cre-recombinase were mated with animals in which exon 1 of PPR is flanked by lox-P sites. In these animals, osteocyte-selective PPR knockout (Ocy-PPRcKO mice) could be induced by administration of tamoxifen. Histological analysis revealed a reduction in trabecular bone and mild osteopenia in Ocy-PPRcKO mice. Reduction of trabeculae number and thickness was also detected by micro-computed tomography analysis whereas bone volume fraction (BV/TV%) was unchanged. These findings were associated with an increase in Sost and sclerostin expression. When Ocy-PPRcKO mice were subjected to a low-calcium diet to induce secondary hyperparathyroidism, their blood calcium levels were significantly lower than littermate controls. Moreover, PTH was unable to suppress Sost and sclerostin expression in the Ocy-PPRcKO animals, suggesting an important role of PTH signaling in osteocytes for proper bone remodeling and calcium homeostasis.

One-Pot Semisynthesis of Exon 1 of the Huntingtin Protein: New Tools for Elucidating the Role of Posttranslational Modifications in the Pathogenesis of Huntington’s Disease

2014 ◽  
Vol 126 (7) ◽  
pp. 1959-1964 ◽  
Author(s):  
Annalisa Ansaloni ◽  
Zhe-Ming Wang ◽  
Jae Sun Jeong ◽  
Francesco Simone Ruggeri ◽  
Giovanni Dietler ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Posttranslational Modifications ◽  
One Pot ◽  
Huntingtin Protein ◽  
Exon 1
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