Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch
Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression prof...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2015-03, Vol.112 (12), p.3770-3775 |
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| creator | Nunes, Diana N. Dias-Neto, Emmanuel Cardó-Vila, Marina Edwards, Julianna K. Dobroff, Andrey S. Giordano, Ricardo J. Mandelin, Jami Brentani, Helena P. Hasselgren, Catrin Yao, Virginia J. Marchiò, Serena Pereira, Carlos A. B. Passetti, Fabio Calin, George A. Sidman, Richard L. Arap, Wadih Pasqualini, Renata |
| description | Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa . Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.
Significance Retinal angiogenesis is a finely tuned biological phenomenon and a major cause of blindness. We studied the regulation of this phenomenon and identified cross-talk involving microRNAs (miRs) that share the same seed sequence, transcription factors, and angiogenesis effectors. In a mouse model of retinopathy of prematurity, we show the down-regulation of all miR-17 family members as an early event in the angiogenic switch, which resulted in increased levels of hypoxia-inducible factor-1α and Vegfa in vitro. Notably, this coordinated regulation did not require the marked quantitative alterations of an individual miR but instead, relied on synchronous changes in members that share the same seed sequence. These results identify potential therapeutic targets in eye diseases with abnormal retinal angiogenesis. |
| doi_str_mv | 10.1073/pnas.1500008112 |
| format | Article |
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Significance Retinal angiogenesis is a finely tuned biological phenomenon and a major cause of blindness. We studied the regulation of this phenomenon and identified cross-talk involving microRNAs (miRs) that share the same seed sequence, transcription factors, and angiogenesis effectors. In a mouse model of retinopathy of prematurity, we show the down-regulation of all miR-17 family members as an early event in the angiogenic switch, which resulted in increased levels of hypoxia-inducible factor-1α and Vegfa in vitro. Notably, this coordinated regulation did not require the marked quantitative alterations of an individual miR but instead, relied on synchronous changes in members that share the same seed sequence. These results identify potential therapeutic targets in eye diseases with abnormal retinal angiogenesis.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1500008112</identifier><identifier>PMID: 25775553</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>3' Untranslated Regions ; Angiogenesis ; animal models ; Animals ; Base Sequence ; Binding sites ; Biological Sciences ; blindness ; Cell Line, Tumor ; Chromosomes ; Disease Models, Animal ; Down-Regulation ; Female ; Gene expression ; Gene Expression Regulation ; Genes, Reporter ; Humans ; hypoxia-inducible factor 1 ; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism ; Male ; Mice ; microRNA ; MicroRNAs ; MicroRNAs - metabolism ; Molecular Sequence Data ; Neovascularization, Pathologic - genetics ; premature birth ; Protein expression ; retinal diseases ; Retinal Neovascularization - genetics ; Retinal Vessels - metabolism ; Retinopathy of Prematurity - pathology ; Sequence Homology, Nucleic Acid ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2015-03, Vol.112 (12), p.3770-3775</ispartof><rights>Volumes 1–89 and 106–112, copyright as a collective work only; author(s) retains copyright to individual articles</rights><rights>Copyright National Academy of Sciences Mar 24, 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-e48f6ef6bc43e9709ccdd0a7b0bace1ab590bb1119ba9984306da0ce3a0c10453</citedby><cites>FETCH-LOGICAL-c524t-e48f6ef6bc43e9709ccdd0a7b0bace1ab590bb1119ba9984306da0ce3a0c10453</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/112/12.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26462153$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26462153$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53769,53771,57995,58228</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25775553$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Nunes, Diana N.</creatorcontrib><creatorcontrib>Dias-Neto, Emmanuel</creatorcontrib><creatorcontrib>Cardó-Vila, Marina</creatorcontrib><creatorcontrib>Edwards, Julianna K.</creatorcontrib><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Giordano, Ricardo J.</creatorcontrib><creatorcontrib>Mandelin, Jami</creatorcontrib><creatorcontrib>Brentani, Helena P.</creatorcontrib><creatorcontrib>Hasselgren, Catrin</creatorcontrib><creatorcontrib>Yao, Virginia J.</creatorcontrib><creatorcontrib>Marchiò, Serena</creatorcontrib><creatorcontrib>Pereira, Carlos A. B.</creatorcontrib><creatorcontrib>Passetti, Fabio</creatorcontrib><creatorcontrib>Calin, George A.</creatorcontrib><creatorcontrib>Sidman, Richard L.</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><title>Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa . Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.
Significance Retinal angiogenesis is a finely tuned biological phenomenon and a major cause of blindness. We studied the regulation of this phenomenon and identified cross-talk involving microRNAs (miRs) that share the same seed sequence, transcription factors, and angiogenesis effectors. In a mouse model of retinopathy of prematurity, we show the down-regulation of all miR-17 family members as an early event in the angiogenic switch, which resulted in increased levels of hypoxia-inducible factor-1α and Vegfa in vitro. Notably, this coordinated regulation did not require the marked quantitative alterations of an individual miR but instead, relied on synchronous changes in members that share the same seed sequence. These results identify potential therapeutic targets in eye diseases with abnormal retinal angiogenesis.</description><subject>3' Untranslated Regions</subject><subject>Angiogenesis</subject><subject>animal models</subject><subject>Animals</subject><subject>Base Sequence</subject><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>blindness</subject><subject>Cell Line, Tumor</subject><subject>Chromosomes</subject><subject>Disease Models, Animal</subject><subject>Down-Regulation</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Genes, Reporter</subject><subject>Humans</subject><subject>hypoxia-inducible factor 1</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>microRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - metabolism</subject><subject>Molecular Sequence Data</subject><subject>Neovascularization, Pathologic - genetics</subject><subject>premature birth</subject><subject>Protein expression</subject><subject>retinal diseases</subject><subject>Retinal Neovascularization - genetics</subject><subject>Retinal Vessels - metabolism</subject><subject>Retinopathy of Prematurity - pathology</subject><subject>Sequence Homology, Nucleic Acid</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc9vFCEUx4nR2Fo9e1JJvHiZ9r0ZBoZLE9P4K2liYu2ZMAyzy2YGtjCzzf73su66rV4kBBL4vC-P75eQ1wjnCKK6WHudzrGGPBrE8gk5RZBYcCbhKTkFKEXRsJKdkBcprTIk6waek5OyFqKu6-qU3N1svVnG4MOcaBfufTGGbh705IKnoaej-1GgoL0e3bClox1bGxN1iWpPrY75zOg5ZXxjqd1YP1Hn6bS0NNrJeT1kbuHCwnpnaLp3k1m-JM96PST76rCfkdvPn35efS2uv3_5dvXxujB1yabCsqbntuetYZWVAqQxXQdatNBqY1G3tYS2RUTZaikbVgHvNBhb5QWB1dUZudzrrud2tJ3JvUU9qHV0o45bFbRTf994t1SLsFGsEg1jmAU-HARiuJttmtTokrHDoL3NbilsoAIJKOT_Uc65bHJCLKPv_0FXYY7Zqd-UYDmVZvf2xZ4yMaQUbX_sG0Htkle75NVD8rni7ePvHvk_UWfg3QHYVR7lsFR5VkJAJt7siVWaQnxQ4IyX-Fih10HpRXRJ3d6UgBwAKymzZb8AkUvIiw</recordid><startdate>20150324</startdate><enddate>20150324</enddate><creator>Nunes, Diana N.</creator><creator>Dias-Neto, Emmanuel</creator><creator>Cardó-Vila, Marina</creator><creator>Edwards, Julianna K.</creator><creator>Dobroff, Andrey S.</creator><creator>Giordano, Ricardo J.</creator><creator>Mandelin, Jami</creator><creator>Brentani, Helena P.</creator><creator>Hasselgren, Catrin</creator><creator>Yao, Virginia J.</creator><creator>Marchiò, Serena</creator><creator>Pereira, Carlos A. B.</creator><creator>Passetti, Fabio</creator><creator>Calin, George A.</creator><creator>Sidman, Richard L.</creator><creator>Arap, Wadih</creator><creator>Pasqualini, Renata</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20150324</creationdate><title>Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch</title><author>Nunes, Diana N. ; Dias-Neto, Emmanuel ; Cardó-Vila, Marina ; Edwards, Julianna K. ; Dobroff, Andrey S. ; Giordano, Ricardo J. ; Mandelin, Jami ; Brentani, Helena P. ; Hasselgren, Catrin ; Yao, Virginia J. ; Marchiò, Serena ; Pereira, Carlos A. B. ; Passetti, Fabio ; Calin, George A. ; Sidman, Richard L. ; Arap, Wadih ; Pasqualini, Renata</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-e48f6ef6bc43e9709ccdd0a7b0bace1ab590bb1119ba9984306da0ce3a0c10453</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>3' Untranslated Regions</topic><topic>Angiogenesis</topic><topic>animal models</topic><topic>Animals</topic><topic>Base Sequence</topic><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>blindness</topic><topic>Cell Line, Tumor</topic><topic>Chromosomes</topic><topic>Disease Models, Animal</topic><topic>Down-Regulation</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Genes, Reporter</topic><topic>Humans</topic><topic>hypoxia-inducible factor 1</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>microRNA</topic><topic>MicroRNAs</topic><topic>MicroRNAs - metabolism</topic><topic>Molecular Sequence Data</topic><topic>Neovascularization, Pathologic - genetics</topic><topic>premature birth</topic><topic>Protein expression</topic><topic>retinal diseases</topic><topic>Retinal Neovascularization - genetics</topic><topic>Retinal Vessels - metabolism</topic><topic>Retinopathy of Prematurity - pathology</topic><topic>Sequence Homology, Nucleic Acid</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Nunes, Diana N.</creatorcontrib><creatorcontrib>Dias-Neto, Emmanuel</creatorcontrib><creatorcontrib>Cardó-Vila, Marina</creatorcontrib><creatorcontrib>Edwards, Julianna K.</creatorcontrib><creatorcontrib>Dobroff, Andrey S.</creatorcontrib><creatorcontrib>Giordano, Ricardo J.</creatorcontrib><creatorcontrib>Mandelin, Jami</creatorcontrib><creatorcontrib>Brentani, Helena P.</creatorcontrib><creatorcontrib>Hasselgren, Catrin</creatorcontrib><creatorcontrib>Yao, Virginia J.</creatorcontrib><creatorcontrib>Marchiò, Serena</creatorcontrib><creatorcontrib>Pereira, Carlos A. B.</creatorcontrib><creatorcontrib>Passetti, Fabio</creatorcontrib><creatorcontrib>Calin, George A.</creatorcontrib><creatorcontrib>Sidman, Richard L.</creatorcontrib><creatorcontrib>Arap, Wadih</creatorcontrib><creatorcontrib>Pasqualini, Renata</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Nunes, Diana N.</au><au>Dias-Neto, Emmanuel</au><au>Cardó-Vila, Marina</au><au>Edwards, Julianna K.</au><au>Dobroff, Andrey S.</au><au>Giordano, Ricardo J.</au><au>Mandelin, Jami</au><au>Brentani, Helena P.</au><au>Hasselgren, Catrin</au><au>Yao, Virginia J.</au><au>Marchiò, Serena</au><au>Pereira, Carlos A. B.</au><au>Passetti, Fabio</au><au>Calin, George A.</au><au>Sidman, Richard L.</au><au>Arap, Wadih</au><au>Pasqualini, Renata</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2015-03-24</date><risdate>2015</risdate><volume>112</volume><issue>12</issue><spage>3770</spage><epage>3775</epage><pages>3770-3775</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Six members of the microRNA-17 (miR-17) family were mapped to three different chromosomes, although they share the same seed sequence and are predicted to target common genes, among which are those encoding hypoxia-inducible factor-1α (HIF1A) and VEGFA. Here, we evaluated the in vivo expression profile of the miR-17 family in the murine retinopathy of prematurity (ROP) model, whereby Vegfa expression is highly enhanced at the early stage of retinal neovascularization, and we found simultaneous reduction of all miR-17 family members at this stage. Using gene reporter assays, we observed binding of these miRs to specific sites in the 3′ UTRs of Hif1a and Vegfa . Furthermore, overexpression of these miRs decreased HIF1A and VEGFA expression in vitro. Our data indicate that this miR-17 family elicits a regulatory synergistic down-regulation of Hif1a and Vegfa expression in this biological model. We propose the existence of a coordinated regulatory network, in which diverse miRs are synchronously regulated to target the Hif1a transcription factor, which in turn, potentiates and reinforces the regulatory effects of the miRs on Vegfa to trigger and sustain a significant physiological response.
Significance Retinal angiogenesis is a finely tuned biological phenomenon and a major cause of blindness. We studied the regulation of this phenomenon and identified cross-talk involving microRNAs (miRs) that share the same seed sequence, transcription factors, and angiogenesis effectors. In a mouse model of retinopathy of prematurity, we show the down-regulation of all miR-17 family members as an early event in the angiogenic switch, which resulted in increased levels of hypoxia-inducible factor-1α and Vegfa in vitro. Notably, this coordinated regulation did not require the marked quantitative alterations of an individual miR but instead, relied on synchronous changes in members that share the same seed sequence. These results identify potential therapeutic targets in eye diseases with abnormal retinal angiogenesis.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>25775553</pmid><doi>10.1073/pnas.1500008112</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated Regions Angiogenesis animal models Animals Base Sequence Binding sites Biological Sciences blindness Cell Line, Tumor Chromosomes Disease Models, Animal Down-Regulation Female Gene expression Gene Expression Regulation Genes, Reporter Humans hypoxia-inducible factor 1 Hypoxia-Inducible Factor 1, alpha Subunit - metabolism Male Mice microRNA MicroRNAs MicroRNAs - metabolism Molecular Sequence Data Neovascularization, Pathologic - genetics premature birth Protein expression retinal diseases Retinal Neovascularization - genetics Retinal Vessels - metabolism Retinopathy of Prematurity - pathology Sequence Homology, Nucleic Acid Vascular Endothelial Growth Factor A - metabolism |
| title | Synchronous down-modulation of miR-17 family members is an early causative event in the retinal angiogenic switch |
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