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  • 1
    Publication Date: 2012-12-22
    Description: How species with similar repertoires of protein-coding genes differ so markedly at the phenotypic level is poorly understood. By comparing organ transcriptomes from vertebrate species spanning ~350 million years of evolution, we observed significant differences in alternative splicing complexity between vertebrate lineages, with the highest complexity in primates. Within 6 million years, the splicing profiles of physiologically equivalent organs diverged such that they are more strongly related to the identity of a species than they are to organ type. Most vertebrate species-specific splicing patterns are cis-directed. However, a subset of pronounced splicing changes are predicted to remodel protein interactions involving trans-acting regulators. These events likely further contributed to the diversification of splicing and other transcriptomic changes that underlie phenotypic differences among vertebrate species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barbosa-Morais, Nuno L -- Irimia, Manuel -- Pan, Qun -- Xiong, Hui Y -- Gueroussov, Serge -- Lee, Leo J -- Slobodeniuc, Valentina -- Kutter, Claudia -- Watt, Stephen -- Colak, Recep -- Kim, TaeHyung -- Misquitta-Ali, Christine M -- Wilson, Michael D -- Kim, Philip M -- Odom, Duncan T -- Frey, Brendan J -- Blencowe, Benjamin J -- 15603/Cancer Research UK/United Kingdom -- A15603/Cancer Research UK/United Kingdom -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2012 Dec 21;338(6114):1587-93. doi: 10.1126/science.1230612.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Banting and Best Department of Medical Research, Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23258890" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Biological Evolution ; Chickens/genetics ; *Evolution, Molecular ; Exons ; Introns ; Lizards/genetics ; Mice/genetics ; Mice, Inbred C57BL/genetics ; Opossums/genetics ; Phenotype ; Platypus/genetics ; Primates/genetics ; RNA Splice Sites ; Regulatory Sequences, Ribonucleic Acid ; Species Specificity ; *Transcriptome ; Vertebrates/*genetics ; Xenopus/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2013-06-07
    Description: Previous investigations of the core gene regulatory circuitry that controls the pluripotency of embryonic stem (ES) cells have largely focused on the roles of transcription, chromatin and non-coding RNA regulators. Alternative splicing represents a widely acting mode of gene regulation, yet its role in regulating ES-cell pluripotency and differentiation is poorly understood. Here we identify the muscleblind-like RNA binding proteins, MBNL1 and MBNL2, as conserved and direct negative regulators of a large program of cassette exon alternative splicing events that are differentially regulated between ES cells and other cell types. Knockdown of MBNL proteins in differentiated cells causes switching to an ES-cell-like alternative splicing pattern for approximately half of these events, whereas overexpression of MBNL proteins in ES cells promotes differentiated-cell-like alternative splicing patterns. Among the MBNL-regulated events is an ES-cell-specific alternative splicing switch in the forkhead family transcription factor FOXP1 that controls pluripotency. Consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933998/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3933998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Hong -- Irimia, Manuel -- Ross, P Joel -- Sung, Hoon-Ki -- Alipanahi, Babak -- David, Laurent -- Golipour, Azadeh -- Gabut, Mathieu -- Michael, Iacovos P -- Nachman, Emil N -- Wang, Eric -- Trcka, Dan -- Thompson, Tadeo -- O'Hanlon, Dave -- Slobodeniuc, Valentina -- Barbosa-Morais, Nuno L -- Burge, Christopher B -- Moffat, Jason -- Frey, Brendan J -- Nagy, Andras -- Ellis, James -- Wrana, Jeffrey L -- Blencowe, Benjamin J -- R01 HG002439/HG/NHGRI NIH HHS/ -- R33 MH087908/MH/NIMH NIH HHS/ -- R33MH087908/MH/NIMH NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2013 Jun 13;498(7453):241-5. doi: 10.1038/nature12270. Epub 2013 Jun 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Banting and Best Department of Medical Research and Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23739326" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing/genetics ; Amino Acid Motifs ; Animals ; Cell Differentiation/genetics ; Cell Line ; *Cellular Reprogramming ; DNA-Binding Proteins/chemistry/deficiency/genetics/*metabolism ; Embryonic Stem Cells/*cytology/*metabolism ; Fibroblasts/cytology/metabolism ; Forkhead Transcription Factors/metabolism ; Gene Knockdown Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Kinetics ; Mice ; RNA-Binding Proteins/chemistry/genetics/*metabolism ; Repressor Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2014-11-04
    Description: Alternative splicing (AS) of precursor RNAs is responsible for greatly expanding the regulatory and functional capacity of eukaryotic genomes. Of the different classes of AS, intron retention (IR) is the least well understood. In plants and unicellular eukaryotes, IR is the most common form of AS, whereas in animals, it is thought to represent the least prevalent form. Using high-coverage poly(A) + RNA-seq data, we observe that IR is surprisingly frequent in mammals, affecting transcripts from as many as three-quarters of multiexonic genes. A highly correlated set of cis features comprising an "IR code" reliably discriminates retained from constitutively spliced introns. We show that IR acts widely to reduce the levels of transcripts that are less or not required for the physiology of the cell or tissue type in which they are detected. This "transcriptome tuning" function of IR acts through both nonsense-mediated mRNA decay and nuclear sequestration and turnover of IR transcripts. We further show that IR is linked to a cross-talk mechanism involving localized stalling of RNA polymerase II (Pol II) and reduced availability of spliceosomal components. Collectively, the results implicate a global checkpoint-type mechanism whereby reduced recruitment of splicing components coupled to Pol II pausing underlies widespread IR-mediated suppression of inappropriately expressed transcripts.
    Electronic ISSN: 1549-5469
    Topics: Biology , Medicine
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