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  • 1
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    Alternative isoform regulation in human tissue transcriptomes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-04
    Description: Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593745/" 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/PMC2593745/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Eric T -- Sandberg, Rickard -- Luo, Shujun -- Khrebtukova, Irina -- Zhang, Lu -- Mayr, Christine -- Kingsmore, Stephen F -- Schroth, Gary P -- Burge, Christopher B -- R01 GM085319/GM/NIGMS NIH HHS/ -- R01 GM085319-01/GM/NIGMS NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- R01 HG002439-07/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Nov 27;456(7221):470-6. doi: 10.1038/nature07509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18978772" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Base Sequence ; Cell Line ; Exons/genetics ; *Gene Expression Profiling ; Humans ; Open Reading Frames/genetics ; Organ Specificity ; Polyadenylation ; Protein Isoforms/*genetics ; RNA, Messenger/*analysis/*genetics ; RNA-Binding Proteins/metabolism ; Repressor Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-10-04
    Description: Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (CTCF), can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Sanjeev -- Kavak, Ersen -- Gregory, Melissa -- Imashimizu, Masahiko -- Shutinoski, Bojan -- Kashlev, Mikhail -- Oberdoerffer, Philipp -- Sandberg, Rickard -- Oberdoerffer, Shalini -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 3;479(7371):74-9. doi: 10.1038/nature10442.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cancer Research, Mouse Cancer Genetics Program, National Cancer Institute at Frederick, Frederick, Maryland 21702, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21964334" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Antigens, CD45/genetics ; Cell Line ; Cells, Cultured ; *DNA Methylation ; Epigenesis, Genetic ; Exons/genetics ; Genome, Human/genetics ; Humans ; Mice ; Protein Binding ; RNA Polymerase II/*metabolism ; RNA Splice Sites/genetics ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/*metabolism ; Saccharomyces cerevisiae/enzymology ; *Transcription, Genetic/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Proliferating cells express mRNAs with shortened 3' untranslated regions and fewer microRNA target sites (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-06-21
    Description: Messenger RNA (mRNA) stability, localization, and translation are largely determined by sequences in the 3' untranslated region (3'UTR). We found a conserved increase in expression of mRNAs terminating at upstream polyadenylation sites after activation of primary murine CD4+ T lymphocytes. This program, resulting in shorter 3'UTRs, is a characteristic of gene expression during immune cell activation and correlates with proliferation across diverse cell types and tissues. Forced expression of full-length 3'UTRs conferred reduced protein expression. In some cases the reduction in protein expression could be reversed by deletion of predicted microRNA target sites in the variably included region. Our data indicate that gene expression is coordinately regulated, such that states of increased proliferation are associated with widespread reductions in the 3'UTR-based regulatory capacity of mRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2587246/" 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/PMC2587246/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sandberg, Rickard -- Neilson, Joel R -- Sarma, Arup -- Sharp, Phillip A -- Burge, Christopher B -- P01 CA042063/CA/NCI NIH HHS/ -- P01 CA042063-22/CA/NCI NIH HHS/ -- P01-CA42063/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 GM034277/GM/NIGMS NIH HHS/ -- R01 GM034277-23/GM/NIGMS NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- R01 HG002439-07/HG/NHGRI NIH HHS/ -- R01-GM34277/GM/NIGMS NIH HHS/ -- R01-HG002439/HG/NHGRI NIH HHS/ -- U19 AI056900/AI/NIAID NIH HHS/ -- U19 AI056900-010001/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2008 Jun 20;320(5883):1643-7. doi: 10.1126/science.1155390.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18566288" target="_blank"〉PubMed〈/a〉
    Keywords: *3' Untranslated Regions ; Animals ; CD4-Positive T-Lymphocytes/cytology/immunology/*metabolism ; Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; Cells, Cultured ; *Gene Expression Regulation ; Humans ; *Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*metabolism ; Oligonucleotide Array Sequence Analysis ; Polyadenylation ; RNA Splicing ; RNA, Messenger/chemistry/genetics/*metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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