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Several mRNAs with variable 3' untranslated regions and different stability encode the human PR264/SC35 splicing factor.

ABSTRACT: We have recently established that several mRNAs encode the PR264/SC35 splicing factor and that their expression is related to that of c-Myb in human hematopoietic cells. We now report that the various PR264 mRNAs whose expression is transactivated by c-Myb proteins encode an identical PR264/SC35 polypeptide. These mRNAs differ only in their 3' untranslated sequences and exhibit significantly different half-lives. We also show that there is a direct correlation between the length of the 3' untranslated region and the stability of the mRNA species. Given that 5' and 3' splice site selection mediated by the PR264/SC35 splicing factor is concentration-dependent, we postulate that alternative splicing of the 3' untranslated sequences might represent another key element in regulating the levels of PR264/SC35 expression during hematopoietic differentiation.

SUBMITTER: Sureau A

PROVIDER: S-EPMC521427 | biostudies-other | 1994 Feb

REPOSITORIES: biostudies-other

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Several mRNAs with variable 3' untranslated regions and different stability encode the human PR264/SC35 splicing factor.

Sureau A A Perbal B B

Proceedings of the National Academy of Sciences of the United States of America 19940201 3

We have recently established that several mRNAs encode the PR264/SC35 splicing factor and that their expression is related to that of c-Myb in human hematopoietic cells. We now report that the various PR264 mRNAs whose expression is transactivated by c-Myb proteins encode an identical PR264/SC35 polypeptide. These mRNAs differ only in their 3' untranslated sequences and exhibit significantly different half-lives. We also show that there is a direct correlation between the length of the 3' untran ...[more]

PMID: 8302870

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Project description:BackgroundThe 3' untranslated regions (3'UTRs) of mRNAs contain cis elements involved in post-transcriptional regulation of gene expression. Over half of all mammalian genes contain multiple polyadenylation sites that lead to different 3'UTRs for a gene. Studies have shown that the alternative polyadenylation (APA) pattern varies across tissues, and is dynamically regulated in proliferating or differentiating cells. Generation of induced pluripotent stem (iPS) cells, in which differentiated cells are reprogrammed to an embryonic stem (ES) cell-like state, has been intensively studied in recent years. However, it is not known how 3'UTRs are regulated during cell reprogramming.Methods/main findingsUsing a computational method that robustly examines APA across DNA microarray data sets, we analyzed 3'UTR dynamics in generation of iPS cells from different cell types. We found that 3'UTRs shorten during reprogramming of somatic cells, the extent of which depends on the type of source cell. By contrast, reprogramming of spermatogonial cells involves 3'UTR lengthening. The alternative polyadenylation sites that are highly responsive to change of cell state in generation of iPS cells are also highly regulated during embryonic development in opposite directions. Compared with other sites, they are more conserved, can lead to longer alternative 3'UTRs, and are associated with more cis elements for polyadenylation. Consistently, reprogramming of somatic cells and germ cells involves significant upregulation and downregulation, respectively, of mRNAs encoding polyadenylation factors, and RNA processing is one of the most significantly regulated biological processes during cell reprogramming. Furthermore, genes containing target sites of ES cell-specific microRNAs (miRNAs) in different portions of 3'UTR are distinctively regulated during cell reprogramming, suggesting impact of APA on miRNA targeting.Conclusions/significanceTaken together, these findings indicate that reprogramming of 3'UTRs by APA, which result from regulation of both general polyadenylation activity and cell type-specific factors and can reset post-transcriptional gene regulatory programs in the cell, is an integral part of iPS cell generation, and the APA pattern can be a good biomarker for cell type and state, useful for sample classification. The results also suggest that perturbation of the mRNA polyadenylation machinery or RNA processing activity may facilitate generation of iPS cells.

Project description:BackgroundOdorant receptor genes constitute the largest gene family in mammalian genomes and this family has been extensively studied in several species, but to date far less attention has been paid to the characterization of their mRNA 3' untranslated regions (3'UTRs). Given the increasing importance of UTRs in the understanding of RNA metabolism, and the growing interest in alternative polyadenylation especially in the nervous system, we aimed at identifying the alternative isoforms of odorant receptor mRNAs generated through 3'UTR variation.ResultsWe implemented a dedicated pipeline using IsoSCM instead of Cufflinks to analyze RNA-Seq data from whole olfactory mucosa of adult mice and obtained an extensive description of the 3'UTR isoforms of odorant receptor mRNAs. To validate our bioinformatics approach, we exhaustively analyzed the 3'UTR isoforms produced from 2 pilot genes, using molecular approaches including northern blot and RNA ligation mediated polyadenylation test. Comparison between datasets further validated the pipeline and confirmed the alternative polyadenylation patterns of odorant receptors. Qualitative and quantitative analyses of the annotated 3' regions demonstrate that 1) Odorant receptor 3'UTRs are longer than previously described in the literature; 2) More than 77% of odorant receptor mRNAs are subject to alternative polyadenylation, hence generating at least 2 detectable 3'UTR isoforms; 3) Splicing events in 3'UTRs are restricted to a limited subset of odorant receptor genes; and 4) Comparison between male and female data shows no sex-specific differences in odorant receptor 3'UTR isoforms.ConclusionsWe demonstrated for the first time that odorant receptor genes are extensively subject to alternative polyadenylation. This ground-breaking change to the landscape of 3'UTR isoforms of Olfr mRNAs opens new avenues for investigating their respective functions, especially during the differentiation of olfactory sensory neurons.

Dataset Information

Several mRNAs with variable 3' untranslated regions and different stability encode the human PR264/SC35 splicing factor.

Publications

Several mRNAs with variable 3' untranslated regions and different stability encode the human PR264/SC35 splicing factor.

Similar Datasets

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