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A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome

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 c...

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Autores principales: Khalil, Ahmad M., Faghihi, Mohammad Ali, Modarresi, Farzaneh, Brothers, Shaun P., Wahlestedt, Claes
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194623/
https://www.ncbi.nlm.nih.gov/pubmed/18213394
http://dx.doi.org/10.1371/journal.pone.0001486
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author Khalil, Ahmad M.
Faghihi, Mohammad Ali
Modarresi, Farzaneh
Brothers, Shaun P.
Wahlestedt, Claes
author_facet Khalil, Ahmad M.
Faghihi, Mohammad Ali
Modarresi, Farzaneh
Brothers, Shaun P.
Wahlestedt, Claes
author_sort Khalil, Ahmad M.
collection PubMed
description 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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spelling pubmed-21946232008-01-23 A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome Khalil, Ahmad M. Faghihi, Mohammad Ali Modarresi, Farzaneh Brothers, Shaun P. Wahlestedt, Claes PLoS One Research Article 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. Public Library of Science 2008-01-23 /pmc/articles/PMC2194623/ /pubmed/18213394 http://dx.doi.org/10.1371/journal.pone.0001486 Text en Khalil et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Khalil, Ahmad M.
Faghihi, Mohammad Ali
Modarresi, Farzaneh
Brothers, Shaun P.
Wahlestedt, Claes
A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title_full A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title_fullStr A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title_full_unstemmed A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title_short A Novel RNA Transcript with Antiapoptotic Function Is Silenced in Fragile X Syndrome
title_sort novel rna transcript with antiapoptotic function is silenced in fragile x syndrome
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2194623/
https://www.ncbi.nlm.nih.gov/pubmed/18213394
http://dx.doi.org/10.1371/journal.pone.0001486
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