749 research outputs found
Targeting long non-coding RNA to therapeutically upregulate gene expression
No full textThe majority of currently available drugs and tool compounds exhibit an inhibitory mechanism of action and there is a relative lack of pharmaceutical agents that are capable of increasing the activity of effectors or pathways for therapeutic benefit. Indeed, the upregulation of many genes, including tumour suppressors, growth factors, transcription factors and genes that are deficient in various genetic diseases, would be desired in specific situations. Recently, key roles for regulatory long non-coding RNAs (lncRNAs) in the regulation of gene expression have begun to emerge. lncRNAs can positively or negatively regulate gene expression and chromatin architecture. Here, we review the current understanding of the mechanisms of action of lncRNAs and their roles in disease, focusing on recent work in the design of inhibitors of the natural antisense transcript (NAT) class of lncRNAs, known as antagoNAT oligonucleotides, and the issues associated with their potential therapeutic application
Emerging Epigenetic Therapies in Neuroscience: Focus on Bromodomain-Containing Drug Targets
No full textClaes Oldenburg : Raw Notes : Documents and Spirits of the Performances : "Stars", "Moveyhouse", "Massage", "The Typewriter" with Annotations by the Author
No full textReproduces Oldenburg's complete unaltered collection of documents (including scripts, notes, instructions, theory) relating to four performances dating from 1963-1968, transcribed from their original form. Includes annotations by the author and examples of the original manuscripts
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Natural antisense and noncoding RNA transcripts as potential drug targets
No full textInformation on the complexity of mammalian RNA transcription has increased greatly in the past few years. Notably, thousands of sense transcripts (conventional protein-coding genes) have antisense transcript partners, most of which are noncoding. Interestingly, a number of antisense transcripts regulate the expression of their sense partners, either in a discordant (antisense knockdown results in sense-transcript elevation) or concordant (antisense knockdown results in concomitant sense-transcript reduction) manner. Two new pharmacological strategies based on the knockdown of antisense RNA transcripts by siRNA (or another RNA targeting principle) are proposed in this review. In the case of discordant regulation, knockdown of antisense transcript elevates the expression of the conventional (sense) gene, thereby conceivably mimicking agonist-activator action. In the case of concordant regulation, knockdown of antisense transcript, or concomitant knockdown of antisense and sense transcripts, results in an additive or even synergistic reduction of the conventional gene expression. Although both strategies have been demonstrated to be valid in cell culture, it remains to be seen whether they provide advantages in other contexts
Functional Characterization of FMR4, a Trans- Acting Long Non-Coding RNA Associated with the Fragile X Locus
No full textCGG repeat expansions in the Fragile X mental retardation 1 (FMR1) gene are responsible for a family of associated disorders characterized by either intellectual disability and autism (Fragile X Syndrome, FXS), or adult-onset neurodegeneration (Fragile X-associated Tremor/Ataxia Syndrome, FXTAS). However, the FMR1 locus is complex and encodes several long noncoding RNAs (lncRNAs), whose expression is altered by repeat expansion mutations. The role of these lncRNAs is thus far unknown; therefore we investigated the functionality of FMR4, which we previously identified. “Full”-length expansions of the FMR1 triplet repeat cause silencing of both FMR1 and FMR4, thus we are interested in potential loss-of-function that may add to phenotypic manifestation of FXS. As cis- regulation of FMR1 by FMR4 was not detected, we sought trans-regulated FMR4 targets in vitro. Gene expression and chromatin immunoprecipitation microarrays identified differentially expressed FMR4-responsive genes. Activities of the polyadenylated and chromatin-associated FMR4 in human neural precursor cells (hNPCs) included regulation of genes involved in cell cycling, differentiation, the ubiquitin-proteasome pathway and a G-protein coupled receptor subunit. FMR4 is expected to share a bidirectional promoter with FMR1, but expression of the two transcripts diverges during peak hNPC proliferation. FMR4 decreases, while FMR1 RNA increases, and these changes are accompanied by corresponding differential expression of FMR4 target genes. By regulating gene expression, FMR4 may promote cellular proliferation rather than differentiation, a role supported by S-phase marker assays. We also identified protein partners of FMR4 using MS2-tagged RNA-immunoprecipitation and mass spectrometry. We therefore propose that FMR4’s function is as a gene-regulatory lncRNA and that this transcript may function in normal development. Closer examination of FMR4 increases our understanding of the role of regulatory lncRNA and the consequences of FMR1 repeat expansions.</p
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Using genomics to understand the nervous system
No full textGenomic approaches have the potential to affect almost every aspect of neuroscience. This review outlines recent advances in genome sequencing and genome variation research as well as the related genomic and bioinformatic technologies. Genomic strategies to study targets and pathways in the nervous system are discussed within the context of drug discovery efforts
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Strategies to Detect Heterologously Expressed Tachykinin Receptors in Xenopus Oocytes
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