Identification of Oct4-activating compounds that enhance reprogramming efficiency
One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramm...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2012-12, Vol.109 (51), p.20853-20858 |
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| creator | Li, Wendong Tian, E Chen, Zhao-Xia Sun, GuoQiang Ye, Peng Yang, Su Lu, Dave Xie, Jun Ho, Thach-Vu Tsark, Walter M. Wang, Charles Horne, David A. Riggs, Arthur D. Yip, M. L. Richard Shi, Yanhong |
| description | One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1 , a gene known to be involved in DNA demethylation. |
| doi_str_mv | 10.1073/pnas.1219181110 |
| format | Article |
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L. Richard ; Shi, Yanhong</creator><creatorcontrib>Li, Wendong ; Tian, E ; Chen, Zhao-Xia ; Sun, GuoQiang ; Ye, Peng ; Yang, Su ; Lu, Dave ; Xie, Jun ; Ho, Thach-Vu ; Tsark, Walter M. ; Wang, Charles ; Horne, David A. ; Riggs, Arthur D. ; Yip, M. L. Richard ; Shi, Yanhong</creatorcontrib><description>One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1 , a gene known to be involved in DNA demethylation.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1219181110</identifier><identifier>PMID: 23213213</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; Benzamides - chemistry ; Benzamides - pharmacology ; Binding sites ; Biochemistry ; Biological Sciences ; Cell Differentiation ; Cell lines ; Cellular Reprogramming - drug effects ; Chemistry, Pharmaceutical - methods ; DNA ; DNA Methylation ; DNA-Binding Proteins - metabolism ; Drug Design ; Embryonic stem cells ; Embryonic Stem Cells - cytology ; Fibroblasts - metabolism ; gene expression ; Gene Expression Regulation, Developmental ; Germ cells ; Green Fluorescent Proteins - metabolism ; Homeodomain Proteins - metabolism ; Humans ; Induced pluripotent stem cells ; Induced Pluripotent Stem Cells - cytology ; luciferase ; Mesenchymal stem cells ; Mice ; Mixed Function Oxygenases ; Molecules ; Morphology ; Nanog Homeobox Protein ; Neural stem cells ; Octamer Transcription Factor-3 - metabolism ; Pluripotent stem cells ; Proteins ; Proto-Oncogene Proteins - metabolism ; Pyridines - chemistry ; Pyridines - pharmacology ; Pyrroles - chemistry ; Pyrroles - pharmacology ; reporter genes ; screening ; Somatic cells ; SOXB1 Transcription Factors - metabolism ; Stem cells ; transcription factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2012-12, Vol.109 (51), p.20853-20858</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Dec 18, 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c525t-8e0f662d2a3732a059dbe1328aaa644e5c419ba40ed08f9b882871e40e668db13</citedby><cites>FETCH-LOGICAL-c525t-8e0f662d2a3732a059dbe1328aaa644e5c419ba40ed08f9b882871e40e668db13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/109/51.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41830629$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41830629$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23213213$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Wendong</creatorcontrib><creatorcontrib>Tian, E</creatorcontrib><creatorcontrib>Chen, Zhao-Xia</creatorcontrib><creatorcontrib>Sun, GuoQiang</creatorcontrib><creatorcontrib>Ye, Peng</creatorcontrib><creatorcontrib>Yang, Su</creatorcontrib><creatorcontrib>Lu, Dave</creatorcontrib><creatorcontrib>Xie, Jun</creatorcontrib><creatorcontrib>Ho, Thach-Vu</creatorcontrib><creatorcontrib>Tsark, Walter M.</creatorcontrib><creatorcontrib>Wang, Charles</creatorcontrib><creatorcontrib>Horne, David A.</creatorcontrib><creatorcontrib>Riggs, Arthur D.</creatorcontrib><creatorcontrib>Yip, M. L. Richard</creatorcontrib><creatorcontrib>Shi, Yanhong</creatorcontrib><title>Identification of Oct4-activating compounds that enhance reprogramming efficiency</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1 , a gene known to be involved in DNA demethylation.</description><subject>Animals</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Binding sites</subject><subject>Biochemistry</subject><subject>Biological Sciences</subject><subject>Cell Differentiation</subject><subject>Cell lines</subject><subject>Cellular Reprogramming - drug effects</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Drug Design</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - cytology</subject><subject>Fibroblasts - metabolism</subject><subject>gene expression</subject><subject>Gene Expression Regulation, Developmental</subject><subject>Germ cells</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Induced pluripotent stem cells</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>luciferase</subject><subject>Mesenchymal stem cells</subject><subject>Mice</subject><subject>Mixed Function Oxygenases</subject><subject>Molecules</subject><subject>Morphology</subject><subject>Nanog Homeobox Protein</subject><subject>Neural stem cells</subject><subject>Octamer Transcription Factor-3 - metabolism</subject><subject>Pluripotent stem cells</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>reporter genes</subject><subject>screening</subject><subject>Somatic cells</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Stem cells</subject><subject>transcription factors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1r3DAQxUVpabZJzz21NfTSi5MZSbalS6GEfgQCoaQ5C1mWd7WsJVeyA_nvK7PbTRMQCOn95jGPR8g7hHOEhl2MXqdzpChRICK8ICsEiWXNJbwkKwDalIJTfkLepLQFAFkJeE1OKKO4nBX5ddVZP7neGT254IvQFzdm4qU2k7vPX35dmDCMYfZdKqaNngrrN9obW0Q7xrCOehgWyPbZwllvHs7Iq17vkn17uE_J3fdvvy9_ltc3P64uv16XpqLVVAoLfV3TjmrWMKqhkl1r81JCa11zbivDUbaag-1A9LIVgooGbX7XtehaZKfky953nNvBdibHiHqnxugGHR9U0E49VbzbqHW4V6yiEniTDT4fDGL4M9s0qcElY3c77W2Yk0IBDGkjsMrop2foNszR53gKKac1ygZopi72lIkhpWj74zIIaqlLLXWpx7ryxIf_Mxz5f_1koDgAy-SjnVQVKgqiWpD3e2SbphCPDEfBoKYy6x_3eq-D0uvokrq7pYA1ALJGCMH-AtzArq8</recordid><startdate>20121218</startdate><enddate>20121218</enddate><creator>Li, Wendong</creator><creator>Tian, E</creator><creator>Chen, Zhao-Xia</creator><creator>Sun, GuoQiang</creator><creator>Ye, Peng</creator><creator>Yang, Su</creator><creator>Lu, Dave</creator><creator>Xie, Jun</creator><creator>Ho, Thach-Vu</creator><creator>Tsark, Walter M.</creator><creator>Wang, Charles</creator><creator>Horne, David A.</creator><creator>Riggs, Arthur D.</creator><creator>Yip, M. 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Richard</creatorcontrib><creatorcontrib>Shi, Yanhong</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>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>Li, Wendong</au><au>Tian, E</au><au>Chen, Zhao-Xia</au><au>Sun, GuoQiang</au><au>Ye, Peng</au><au>Yang, Su</au><au>Lu, Dave</au><au>Xie, Jun</au><au>Ho, Thach-Vu</au><au>Tsark, Walter M.</au><au>Wang, Charles</au><au>Horne, David A.</au><au>Riggs, Arthur D.</au><au>Yip, M. L. Richard</au><au>Shi, Yanhong</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of Oct4-activating compounds that enhance reprogramming efficiency</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2012-12-18</date><risdate>2012</risdate><volume>109</volume><issue>51</issue><spage>20853</spage><epage>20858</epage><pages>20853-20858</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>One of the hurdles for practical application of induced pluripotent stem cells (iPSC) is the low efficiency and slow process of reprogramming. Octamer-binding transcription factor 4 (Oct4) has been shown to be an essential regulator of embryonic stem cell (ESC) pluripotency and key to the reprogramming process. To identify small molecules that enhance reprogramming efficiency, we performed a cell-based high-throughput screening of chemical libraries. One of the compounds, termed Oct4-activating compound 1 (OAC1), was found to activate both Oct4 and Nanog promoter-driven luciferase reporter genes. Furthermore, when added to the reprogramming mixture along with the quartet reprogramming factors (Oct4, Sox2, c-Myc, and Klf4), OAC1 enhanced the iPSC reprogramming efficiency and accelerated the reprogramming process. Two structural analogs of OAC1 also activated Oct4 and Nanog promoters and enhanced iPSC formation. The iPSC colonies derived using the Oct4-activating compounds along with the quartet factors exhibited typical ESC morphology, gene-expression pattern, and developmental potential. OAC1 seems to enhance reprogramming efficiency in a unique manner, independent of either inhibition of the p53-p21 pathway or activation of the Wnt-β-catenin signaling. OAC1 increases transcription of the Oct4-Nanog-Sox2 triad and Tet1 , a gene known to be involved in DNA demethylation.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>23213213</pmid><doi>10.1073/pnas.1219181110</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Benzamides - chemistry Benzamides - pharmacology Binding sites Biochemistry Biological Sciences Cell Differentiation Cell lines Cellular Reprogramming - drug effects Chemistry, Pharmaceutical - methods DNA DNA Methylation DNA-Binding Proteins - metabolism Drug Design Embryonic stem cells Embryonic Stem Cells - cytology Fibroblasts - metabolism gene expression Gene Expression Regulation, Developmental Germ cells Green Fluorescent Proteins - metabolism Homeodomain Proteins - metabolism Humans Induced pluripotent stem cells Induced Pluripotent Stem Cells - cytology luciferase Mesenchymal stem cells Mice Mixed Function Oxygenases Molecules Morphology Nanog Homeobox Protein Neural stem cells Octamer Transcription Factor-3 - metabolism Pluripotent stem cells Proteins Proto-Oncogene Proteins - metabolism Pyridines - chemistry Pyridines - pharmacology Pyrroles - chemistry Pyrroles - pharmacology reporter genes screening Somatic cells SOXB1 Transcription Factors - metabolism Stem cells transcription factors |
| title | Identification of Oct4-activating compounds that enhance reprogramming efficiency |
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