Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA repeat expansion is the genetic basis for a growing number of neurological disorders. While the largest subset of these diseases results in an increase in the length of a polyglutamine tract in the protein encoded by the affected gene, the most common form of inherited mental retardation, fragile X syndrome, and the most common inherited ataxia, Friedreich's ataxia, are both caused by expansions that are transcribed but not translated. These expansions both decrease expression of the gene in which the expanded repeat is located, but they do so by quite different mechanisms. In fragile X syndrome, CGG. CCG expansion in the 5' untranslated region of the FMR1 gene leads to hypermethylation of the repeats and the adjacent CpG-rich promoter. Methylation prevents the binding of the transcription factor alpha-Pal/NRF-1, and may indirectly affect the binding of other factors via the formation of transcriptionally silent chromatin. In Friedreich's ataxia, GAA. TTC expansion in an intron of the FRDA gene reduces expression by interfering with transcription elongation. The model that best describes the available data is transcription-driven formation of a transient purine. purine. pyrimidine DNA triplex behind an advancing RNA polymerase. This structure lassoes the RNA polymerase that caused it, trapping the enzyme on the template.
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PMID:Fragile X syndrome and Friedreich's ataxia: two different paradigms for repeat induced transcript insufficiency. 1171 74

MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a posttranscriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97% of the genome is noncoding DNA, which varies from one individual to another, and changes in these sequences are frequently noted to manifest clinical and circumstantial malfunction. Type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA is a new class of miRNAs derived from the processing of nonproteincoding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, neither function nor application has been reported. Here, we show for the first time that intron-derived miRNA is not only able to induce RNAi in mammalian cells but also in fish, chicken embryos, and adult mice, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies.
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PMID:Gene silencing in vitro and in vivo using intronic microRNAs. 1695 84

Several genome-wide transcriptomics efforts have shown that a large percentage of the mammalian genome is transcribed into RNAs, however, only a small percentage (1-2%) of these RNAs is translated into proteins. Currently there is an intense interest in characterizing the function of the different classes of noncoding RNAs and their relevance to human disease. Using genomic approaches we discovered FMR4, a primate-specific noncoding RNA transcript (2.4 kb) that resides upstream and likely shares a bidirectional promoter with FMR1. FMR4 is a product of RNA polymerase II and has a similar half-life to FMR1. The CGG expansion in the 5' UTR of FMR1 appears to affect transcription in both directions as we found FMR4, similar to FMR1, to be silenced in fragile X patients and up-regulated in premutation carriers. Knockdown of FMR4 by several siRNAs did not affect FMR1 expression, nor vice versa, suggesting that FMR4 is not a direct regulatory transcript for FMR1. However, FMR4 markedly affected human cell proliferation in vitro; siRNAs knockdown of FMR4 resulted in alterations in the cell cycle and increased apoptosis, while the overexpression of FMR4 caused an increase in cell proliferation. Collectively, our results demonstrate an antiapoptotic function of FMR4 and provide evidence that a well-studied genomic locus can show unexpected functional complexity. It cannot be excluded that altered FMR4 expression might contribute to aspects of the clinical presentation of fragile X syndrome and/or related disorders.
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PMID:A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome. 1821 94

MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a posttranscriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97% of the genome is noncoding DNA, which varies from one individual to another, and changes in these sequences are frequently noted to manifest in clinical and circumstantial malfunction; for example, type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA is a new class of miRNAs derived from the processing of nonprotein-coding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, their functions and applications have not been reported. Here, we show for the first time that intron-derived miRNA is not only able to induce RNAi in mammalian cells, but also in fish, chicken embryos, and adult mice cells, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies.
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PMID:Gene silencing in vitro and in vivo using intronic microRNAs. 2300 11

MicroRNAs (miRNAs) are small, single-stranded noncoding RNAs important in many biological processes through posttranscriptional modification of complementary intracellular messenger RNAs (mRNAs). MiRNAs have been reported to induce RNA interference (RNAi), by utilizing the miRNA-induced silencing complex (miRISC) to target mRNAs. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97 % of the genome is noncoding DNA and changes in these sequences are frequently noted to manifest in clinical and circumstantial malfunction; for example, type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA (mirtrons) is a class of miRNAs derived from the processing of non-protein-coding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, their functions and applications have not been reported. It is notable that there are different, but still highly conserved, mirtrons in mammalian than in invertebrates, and could be an indication that mirtrons are an evolutionary precursor to existing miRNA biogenesis pathways. Here, we show that intron-derived miRNA is not only able to induce RNAi in mammalian cells but also in fish, chicken embryos, and adult mice cells, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies.
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PMID:Gene silencing in vitro and in vivo using intronic microRNAs. 2531 61

MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) that contain either complete or partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. Numerous miRNAs have been reported to induce RNA interference (RNAi), a post-transcriptional gene-silencing mechanism. Recent evidence also indicates that they are involved in the transcriptional regulation of genome activities. They were first discovered in Caenorhabditis elegans as native RNA fragments that modulate a wide range of genetic regulatory pathways during embryonic development, and are now recognized as small gene silencers transcribed from the noncoding regions of a genome. In humans, nearly 97% of the genome is noncoding DNA, which varies from one individual to another, and changes in these sequences are frequently noted to manifest in clinical and circumstantial malfunction; for example, type 2 myotonic dystrophy and fragile X syndrome were found to be associated with miRNAs derived from introns. Intronic miRNA is a new class of miRNAs derived from the processing of non-protein-coding regions of gene transcripts. The intronic miRNAs differ uniquely from previously described intergenic miRNAs in the requirement of RNA polymerase (Pol)-II and spliceosomal components for its biogenesis. Several kinds of intronic miRNAs have been identified in C. elegans, mouse, and human cells; however, their functions and applications have not been reported. Here, we show for the first time that intron-derived miRNA is not only able to induce RNAi in mammalian cells but also in fish, chicken embryos, and adult mice cells, demonstrating the evolutionary preservation of this gene regulation system in vivo. These miRNA-mediated animal models provide artificial means to reproduce the mechanisms of miRNA-induced disease in vivo and will shed further light on miRNA-related therapies.
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PMID:Gene Silencing In Vitro and In Vivo Using Intronic MicroRNAs. 2943 27

Fragile X syndrome (FXS) is the most common congenital hereditary disease of low intelligence after Down syndrome. Its main pathogenic gene is fragile X mental retardation 1 (FMR1) gene associated with intellectual disability, autism, and fragile X-related primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). FMR1 gene transcription leads to the absence of fragile X mental retardation protein (FMRP). How to relieve or cure disorders associated with FXS has also become a clinically disturbing problem. Previous studies have recently shown that long noncoding RNAs (lncRNAs) contribute to the pathogenesis. And it has been identified that several lncRNAs including FMR4, FMR5, and FMR6 contribute to developing FXPOI/FXTAS, originating from the FMR1 gene locus. FMR4 is a product of RNA polymerase II and can regulate the expression of relevant genes during differentiation of human neural precursor cells. FMR5 is a sense-oriented transcript while FMR6 is an antisense lncRNA produced by the 3' UTR of FMR1. FMR6 is likely to contribute to developing FXPOI, and it overlaps exons 15-17 of FMR1 as well as two microRNA binding sites. Additionally, BC1 can bind FMRP to form an inhibitory complex and lncRNA TUG1 also can control axonal development by directly interacting with FMRP through modulating SnoN-Ccd1 pathway. Therefore, these lncRNAs provide pharmaceutical targets and novel biomarkers. This review will: (1) describe the clinical manifestations and traditional pathogenesis of FXS and FXTAS/FXPOI; (2) summarize what is known about the role of lncRNAs in the pathogenesis of FXS and FXTAS/FXPOI; and (3) provide an outlook of potential effects and future directions of lncRNAs in FXS and FXTAS/FXPOI researches.
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PMID:Long Noncoding RNA Can Be a Probable Mechanism and a Novel Target for Diagnosis and Therapy in Fragile X Syndrome. 3119 98