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  • 1
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    Alternative isoform regulation in human tissue transcriptomes (2008)
    Nature Publishing Group (NPG)
    Details
    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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    Evolutionary dynamics of gene and isoform regulation in Mammalian tissues (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-12-22
    Description: Most mammalian genes produce multiple distinct messenger RNAs through alternative splicing, but the extent of splicing conservation is not clear. To assess tissue-specific transcriptome variation across mammals, we sequenced complementary DNA from nine tissues from four mammals and one bird in biological triplicate, at unprecedented depth. We find that while tissue-specific gene expression programs are largely conserved, alternative splicing is well conserved in only a subset of tissues and is frequently lineage-specific. Thousands of previously unknown, lineage-specific, and conserved alternative exons were identified; widely conserved alternative exons had signatures of binding by MBNL, PTB, RBFOX, STAR, and TIA family splicing factors, implicating them as ancestral mammalian splicing regulators. Our data also indicate that alternative splicing often alters protein phosphorylatability, delimiting the scope of kinase signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568499/" 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/PMC3568499/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Merkin, Jason -- Russell, Caitlin -- Chen, Ping -- Burge, Christopher B -- OD011092/OD/NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2012 Dec 21;338(6114):1593-9. doi: 10.1126/science.1228186.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23258891" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Biological Evolution ; Cattle ; Chickens ; Conserved Sequence ; DNA, Complementary ; DNA-Binding Proteins/metabolism ; *Evolution, Molecular ; Exons ; Gene Expression Profiling ; *Gene Expression Regulation ; Introns ; Macaca mulatta ; Male ; Mammals/*genetics ; Mice ; Models, Genetic ; Phosphorylation ; Phylogeny ; Protein Isoforms/chemistry/*genetics/metabolism ; Protein Kinases/genetics/metabolism ; RNA Splice Sites ; RNA Splicing ; RNA-Binding Proteins/metabolism ; Rats ; Sequence Analysis, DNA ; *Transcriptome
    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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  • 3
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    Predictive identification of exonic splicing enhancers in human genes (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-07-13
    Description: Specific short oligonucleotide sequences that enhance pre-mRNA splicing when present in exons, termed exonic splicing enhancers (ESEs), play important roles in constitutive and alternative splicing. A computational method, RESCUE-ESE, was developed that predicts which sequences have ESE activity by statistical analysis of exon-intron and splice site composition. When large data sets of human gene sequences were used, this method identified 10 predicted ESE motifs. Representatives of all 10 motifs were found to display enhancer activity in vivo, whereas point mutants of these sequences exhibited sharply reduced activity. The motifs identified enable prediction of the splicing phenotypes of exonic mutations in human genes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fairbrother, William G -- Yeh, Ru-Fang -- Sharp, Phillip A -- Burge, Christopher B -- 1 R01 HG02439-01/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2002 Aug 9;297(5583):1007-13. Epub 2002 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Center for Cancer Research, 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/12114529" target="_blank"〉PubMed〈/a〉
    Keywords: Computational Biology ; Consensus Sequence ; DNA, Complementary ; Databases, Nucleic Acid ; *Exons ; *Genes ; *Genome, Human ; Humans ; Hypoxanthine Phosphoribosyltransferase/genetics ; Introns ; Oligonucleotides/genetics ; Point Mutation ; *RNA Splicing ; *Regulatory Sequences, Nucleic Acid ; Sequence Analysis, DNA
    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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  • 4
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    Vertebrate microRNA genes (2003)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2003-03-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Lee P -- Glasner, Margaret E -- Yekta, Soraya -- Burge, Christopher B -- Bartel, David P -- New York, N.Y. -- Science. 2003 Mar 7;299(5612):1540.〈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/12624257" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis/genetics ; Computational Biology ; Conserved Sequence ; Genome ; Genome, Human ; Humans ; Likelihood Functions ; MicroRNAs/chemistry/*genetics ; Nucleic Acid Conformation ; RNA Precursors/chemistry/genetics ; Takifugu/genetics ; Vertebrates/*genetics ; Zebrafish/genetics
    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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  • 5
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    The widespread impact of mammalian MicroRNAs on mRNA repression and evolution (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-11-26
    Description: Thousands of mammalian messenger RNAs are under selective pressure to maintain 7-nucleotide sites matching microRNAs (miRNAs). We found that these conserved targets are often highly expressed at developmental stages before miRNA expression and that their levels tend to fall as the miRNA that targets them begins to accumulate. Nonconserved sites, which outnumber the conserved sites 10 to 1, also mediate repression. As a consequence, genes preferentially expressed at the same time and place as a miRNA have evolved to selectively avoid sites matching the miRNA. This phenomenon of selective avoidance extends to thousands of genes and enables spatial and temporal specificities of miRNAs to be revealed by finding tissues and developmental stages in which messages with corresponding sites are expressed at lower levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farh, Kyle Kai-How -- Grimson, Andrew -- Jan, Calvin -- Lewis, Benjamin P -- Johnston, Wendy K -- Lim, Lee P -- Burge, Christopher B -- Bartel, David P -- New York, N.Y. -- Science. 2005 Dec 16;310(5755):1817-21. Epub 2005 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, and Howard Hughes Medical Institute, 9 Cambridge Center, Cambridge, MA 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16308420" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Differentiation ; Conserved Sequence ; *Evolution, Molecular ; Gene Expression Profiling ; *Gene Expression Regulation ; Humans ; Mammals/*genetics ; Mice ; MicroRNAs/*metabolism ; Molecular Sequence Data ; Muscle Fibers, Skeletal/cytology/metabolism ; Organ Specificity ; RNA Stability ; RNA, Messenger/*genetics/metabolism ; Rats ; Species Specificity ; Untranslated Regions ; Zebrafish/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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  • 6
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    Promoter directionality is controlled by U1 snRNP and polyadenylation signals (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-25
    Description: Transcription of the mammalian genome is pervasive, but productive transcription outside of protein-coding genes is limited by unknown mechanisms. In particular, although RNA polymerase II (RNAPII) initiates divergently from most active gene promoters, productive elongation occurs primarily in the sense-coding direction. Here we show in mouse embryonic stem cells that asymmetric sequence determinants flanking gene transcription start sites control promoter directionality by regulating promoter-proximal cleavage and polyadenylation. We find that upstream antisense RNAs are cleaved and polyadenylated at poly(A) sites (PASs) shortly after initiation. De novo motif analysis shows PAS signals and U1 small nuclear ribonucleoprotein (snRNP) recognition sites to be the most depleted and enriched sequences, respectively, in the sense direction relative to the upstream antisense direction. These U1 snRNP sites and PAS sites are progressively gained and lost, respectively, at the 5' end of coding genes during vertebrate evolution. Functional disruption of U1 snRNP activity results in a dramatic increase in promoter-proximal cleavage events in the sense direction with slight increases in the antisense direction. These data suggest that a U1-PAS axis characterized by low U1 snRNP recognition and a high density of PASs in the upstream antisense region reinforces promoter directionality by promoting early termination in upstream antisense regions, whereas proximal sense PAS signals are suppressed by U1 snRNP. We propose that the U1-PAS axis limits pervasive transcription throughout the genome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720719/" 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/PMC3720719/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Almada, Albert E -- Wu, Xuebing -- Kriz, Andrea J -- Burge, Christopher B -- Sharp, Phillip A -- GM-085319/GM/NIGMS NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 CA133404/CA/NCI NIH HHS/ -- R01 GM034277/GM/NIGMS NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- R01-CA133404/CA/NCI NIH HHS/ -- R01-GM34277/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jul 18;499(7458):360-3. doi: 10.1038/nature12349. Epub 2013 Jun 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉David H. Koch Institute for Integrative Cancer Research, 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/23792564" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Evolution, Molecular ; Mice ; *Polyadenylation ; *Promoter Regions, Genetic ; RNA Cleavage ; RNA, Antisense/metabolism ; Ribonucleoprotein, U1 Small Nuclear/*metabolism ; *Transcription Elongation, Genetic ; Transcription Termination, Genetic
    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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  • 7
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    MBNL proteins repress ES-cell-specific alternative splicing and reprogramming (2013)
    Nature Publishing Group (NPG)
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    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
    Published by Nature Publishing Group (NPG)
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  • 8
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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
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  • 9
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    Identification and analysis of alternative splicing events conserved in human and mouse (2005)
    National Academy of Sciences
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    Publication Date: 2005-02-11
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    A transcriptional response to replication status mediated by the conserved bacterial replication protein DnaA (2005)
    National Academy of Sciences
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    Publication Date: 2005-08-24
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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