MicroRNAs to Nanog , Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation
MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying ass...
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| Veröffentlicht in: | Nature 2008-10, Vol.455 (7216), p.1124-1128 |
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| creator | Rigoutsos, Isidore Tay, Yvonne Zhang, Jinqiu Thomson, Andrew M Lim, Bing |
| description | MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region. |
| doi_str_mv | 10.1038/nature07299 |
| format | Article |
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For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>EISSN: 1476-4679</identifier><identifier>DOI: 10.1038/nature07299</identifier><identifier>PMID: 18806776</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Amino acids ; Animals ; Biological and medical sciences ; Blotting, Western ; Cell differentiation ; Cell Differentiation - genetics ; Cell differentiation, maturation, development, hematopoiesis ; Cell Line ; Cell physiology ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Embryonic Stem Cells - cytology ; Embryonic Stem Cells - metabolism ; Embryos ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Gene Expression Regulation, Developmental ; HMGB Proteins - genetics ; HMGB Proteins - metabolism ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humanities and Social Sciences ; letter ; Messenger RNA ; Mice ; MicroRNAs - genetics ; MicroRNAs - metabolism ; Molecular and cellular biology ; multidisciplinary ; Mutation ; Nanog Homeobox Protein ; Octamer Transcription Factor-3 - genetics ; Octamer Transcription Factor-3 - metabolism ; Open Reading Frames - genetics ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; SOXB1 Transcription Factors ; Stem cell research ; Stem cells ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Nature, 2008-10, Vol.455 (7216), p.1124-1128</ispartof><rights>Macmillan Publishers Limited. 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For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region.</description><subject>Amino acids</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Cell differentiation</subject><subject>Cell Differentiation - genetics</subject><subject>Cell differentiation, maturation, development, hematopoiesis</subject><subject>Cell Line</subject><subject>Cell physiology</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Embryos</subject><subject>Fundamental and applied biological sciences. 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For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3′ untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3′ untranslated region.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>18806776</pmid><doi>10.1038/nature07299</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature, 2008-10, Vol.455 (7216), p.1124-1128 |
| issn | 0028-0836 1476-4687 1476-4679 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_904473320 |
| source | MEDLINE; SpringerLink Journals; Nature |
| subjects | Amino acids Animals Biological and medical sciences Blotting, Western Cell differentiation Cell Differentiation - genetics Cell differentiation, maturation, development, hematopoiesis Cell Line Cell physiology DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Embryonic Stem Cells - cytology Embryonic Stem Cells - metabolism Embryos Fundamental and applied biological sciences. Psychology Gene expression Gene Expression Regulation, Developmental HMGB Proteins - genetics HMGB Proteins - metabolism Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humanities and Social Sciences letter Messenger RNA Mice MicroRNAs - genetics MicroRNAs - metabolism Molecular and cellular biology multidisciplinary Mutation Nanog Homeobox Protein Octamer Transcription Factor-3 - genetics Octamer Transcription Factor-3 - metabolism Open Reading Frames - genetics Proteins Reverse Transcriptase Polymerase Chain Reaction Ribonucleic acid RNA Science Science (multidisciplinary) SOXB1 Transcription Factors Stem cell research Stem cells Transcription Factors - genetics Transcription Factors - metabolism |
| title | MicroRNAs to Nanog , Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T05%3A50%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MicroRNAs%20to%20Nanog%20,%20Oct4%20and%20Sox2%20coding%20regions%20modulate%20embryonic%20stem%20cell%20differentiation&rft.jtitle=Nature&rft.au=Rigoutsos,%20Isidore&rft.date=2008-10-23&rft.volume=455&rft.issue=7216&rft.spage=1124&rft.epage=1128&rft.pages=1124-1128&rft.issn=0028-0836&rft.eissn=1476-4687&rft.coden=NATUAS&rft_id=info:doi/10.1038/nature07299&rft_dat=%3Cgale_proqu%3EA188899934%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=204463997&rft_id=info:pmid/18806776&rft_galeid=A188899934&rfr_iscdi=true |