A noncoding RNA modulator potentiates phenylalanine metabolism in mice
The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA and human associate with phenylalanine hydroxylase (PAH). -knockout mice exhibited excessive blood phenylalanine (Phe), musty...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2021-08, Vol.373 (6555), p.662-673 |
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| creator | Li, Yajuan Tan, Zhi Zhang, Yaohua Zhang, Zhao Hu, Qingsong Liang, Ke Jun, Yao Ye, Youqiong Li, Yi-Chuan Li, Chunlai Liao, Lan Xu, Jianming Xing, Zhen Pan, Yinghong Chatterjee, Sujash S Nguyen, Tina K Hsiao, Heidi Egranov, Sergey D Putluri, Nagireddy Coarfa, Cristian Hawke, David H Gunaratne, Preethi H Tsai, Kuang-Lei Han, Leng Hung, Mien-Chie Calin, George A Namour, Fares Guéant, Jean-Louis Muntau, Ania C Blau, Nenad Sutton, V Reid Schiff, Manuel Feillet, François Zhang, Shuxing Lin, Chunru Yang, Liuqing |
| description | The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA
and human
associate with phenylalanine hydroxylase (PAH).
-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.
depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically,
modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-
mimics reduced excessive Phe in
and
mice and improved the Phe tolerance of these mice. |
| doi_str_mv | 10.1126/science.aba4991 |
| format | Article |
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and human
associate with phenylalanine hydroxylase (PAH).
-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.
depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically,
modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-
mimics reduced excessive Phe in
and
mice and improved the Phe tolerance of these mice.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.aba4991</identifier><identifier>PMID: 34353949</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Acetylgalactosamine ; Animal models ; Animals ; Biopterins - analogs & derivatives ; Biopterins - metabolism ; Biopterins - therapeutic use ; Cell differentiation ; Depletion ; Diet ; Disease Models, Animal ; Enzymatic activity ; Female ; Growth rate ; Hepatocytes ; Hepatocytes - metabolism ; Humans ; Hydroxylase ; Liver ; Liver - embryology ; Liver - metabolism ; Male ; Metabolic disorders ; Metabolism ; Mice ; Mice, Knockout ; Mimicry ; Mutation ; Nucleic Acid Conformation ; Nutrition therapy ; Patients ; Phenotypes ; Phenylalanine ; Phenylalanine - administration & dosage ; Phenylalanine - metabolism ; Phenylalanine 4-monooxygenase ; Phenylalanine Hydroxylase - deficiency ; Phenylalanine Hydroxylase - genetics ; Phenylalanine Hydroxylase - metabolism ; Phenylketonuria ; Phenylketonurias - drug therapy ; Phenylketonurias - genetics ; Phenylketonurias - metabolism ; Pigmentation ; Pluripotency ; Protein Binding ; Ribonucleic acid ; RNA ; RNA, Long Noncoding - chemistry ; RNA, Long Noncoding - genetics ; RNA, Long Noncoding - metabolism ; RNA, Long Noncoding - therapeutic use ; Seizures ; Signs and symptoms ; Stem cells ; Substrates</subject><ispartof>Science (American Association for the Advancement of Science), 2021-08, Vol.373 (6555), p.662-673</ispartof><rights>Copyright © 2021, American Association for the Advancement of Science.</rights><rights>Copyright © 2021, American Association for the Advancement of Science</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-1a498da1ae31a51053eedd78e57ea83c4d54d49ac282fa34de51e727525b42473</citedby><cites>FETCH-LOGICAL-c487t-1a498da1ae31a51053eedd78e57ea83c4d54d49ac282fa34de51e727525b42473</cites><orcidid>0000-0002-2900-8378 ; 0000-0003-4317-4740 ; 0000-0002-6450-8554 ; 0000-0002-7380-2640 ; 0000-0001-8332-4710 ; 0000-0001-7334-1787 ; 0000-0001-8272-232X ; 0000-0002-8208-9162 ; 0000-0003-1897-9889 ; 0000-0003-1895-0285 ; 0000-0002-9267-4701 ; 0000-0002-6102-7843 ; 0000-0002-1795-1051 ; 0000-0002-8717-469X ; 0000-0003-2328-6956 ; 0000-0002-3757-8469 ; 0000-0002-6518-474X ; 0000-0003-4488-7400 ; 0000-0002-9741-591X ; 0000-0002-5428-4219 ; 0000-0001-8994-649X ; 0000-0002-6473-8229 ; 0000-0003-1418-3576 ; 0000-0002-6478-8752 ; 0000-0002-4183-4939</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,2884,2885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34353949$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Yajuan</creatorcontrib><creatorcontrib>Tan, Zhi</creatorcontrib><creatorcontrib>Zhang, Yaohua</creatorcontrib><creatorcontrib>Zhang, Zhao</creatorcontrib><creatorcontrib>Hu, Qingsong</creatorcontrib><creatorcontrib>Liang, Ke</creatorcontrib><creatorcontrib>Jun, Yao</creatorcontrib><creatorcontrib>Ye, Youqiong</creatorcontrib><creatorcontrib>Li, Yi-Chuan</creatorcontrib><creatorcontrib>Li, Chunlai</creatorcontrib><creatorcontrib>Liao, Lan</creatorcontrib><creatorcontrib>Xu, Jianming</creatorcontrib><creatorcontrib>Xing, Zhen</creatorcontrib><creatorcontrib>Pan, Yinghong</creatorcontrib><creatorcontrib>Chatterjee, Sujash S</creatorcontrib><creatorcontrib>Nguyen, Tina K</creatorcontrib><creatorcontrib>Hsiao, Heidi</creatorcontrib><creatorcontrib>Egranov, Sergey D</creatorcontrib><creatorcontrib>Putluri, Nagireddy</creatorcontrib><creatorcontrib>Coarfa, Cristian</creatorcontrib><creatorcontrib>Hawke, David H</creatorcontrib><creatorcontrib>Gunaratne, Preethi H</creatorcontrib><creatorcontrib>Tsai, Kuang-Lei</creatorcontrib><creatorcontrib>Han, Leng</creatorcontrib><creatorcontrib>Hung, Mien-Chie</creatorcontrib><creatorcontrib>Calin, George A</creatorcontrib><creatorcontrib>Namour, Fares</creatorcontrib><creatorcontrib>Guéant, Jean-Louis</creatorcontrib><creatorcontrib>Muntau, Ania C</creatorcontrib><creatorcontrib>Blau, Nenad</creatorcontrib><creatorcontrib>Sutton, V Reid</creatorcontrib><creatorcontrib>Schiff, Manuel</creatorcontrib><creatorcontrib>Feillet, François</creatorcontrib><creatorcontrib>Zhang, Shuxing</creatorcontrib><creatorcontrib>Lin, Chunru</creatorcontrib><creatorcontrib>Yang, Liuqing</creatorcontrib><title>A noncoding RNA modulator potentiates phenylalanine metabolism in mice</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA
and human
associate with phenylalanine hydroxylase (PAH).
-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.
depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically,
modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-
mimics reduced excessive Phe in
and
mice and improved the Phe tolerance of these mice.</description><subject>Acetylgalactosamine</subject><subject>Animal models</subject><subject>Animals</subject><subject>Biopterins - analogs & derivatives</subject><subject>Biopterins - metabolism</subject><subject>Biopterins - therapeutic use</subject><subject>Cell differentiation</subject><subject>Depletion</subject><subject>Diet</subject><subject>Disease Models, Animal</subject><subject>Enzymatic activity</subject><subject>Female</subject><subject>Growth rate</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Hydroxylase</subject><subject>Liver</subject><subject>Liver - embryology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mimicry</subject><subject>Mutation</subject><subject>Nucleic Acid Conformation</subject><subject>Nutrition therapy</subject><subject>Patients</subject><subject>Phenotypes</subject><subject>Phenylalanine</subject><subject>Phenylalanine - administration & dosage</subject><subject>Phenylalanine - metabolism</subject><subject>Phenylalanine 4-monooxygenase</subject><subject>Phenylalanine Hydroxylase - deficiency</subject><subject>Phenylalanine Hydroxylase - genetics</subject><subject>Phenylalanine Hydroxylase - metabolism</subject><subject>Phenylketonuria</subject><subject>Phenylketonurias - drug therapy</subject><subject>Phenylketonurias - genetics</subject><subject>Phenylketonurias - metabolism</subject><subject>Pigmentation</subject><subject>Pluripotency</subject><subject>Protein Binding</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>RNA, Long Noncoding - chemistry</subject><subject>RNA, Long Noncoding - genetics</subject><subject>RNA, Long Noncoding - metabolism</subject><subject>RNA, Long Noncoding - therapeutic use</subject><subject>Seizures</subject><subject>Signs and symptoms</subject><subject>Stem cells</subject><subject>Substrates</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkM1LAzEQxYMotn6cvcmC59V8NpuLUMSqIAqi5zBNppqym9TNVuh_b8Qqehjm8N785vEIOWH0nDE-ucguYHR4DnOQxrAdMmbUqNpwKnbJmFIxqRuq1Ygc5LyktGhG7JORkEIJI82YzKZVTNElH-Jr9fQwrbrk1y0Mqa9WacA4BBgwV6s3jJsWWoghYtXhAPPUhtxVIVZdcHhE9hbQZjze7kPyMrt-vrqt7x9v7q6m97WTjR5qVlI2HhigYKAYVQLRe92g0giNcNIr6aUBxxu-ACE9Koaaa8XVXHKpxSG5_Oau1vMOvSsBe2jtqg8d9BubINj_Sgxv9jV9WKNZAagCONsC-vS-xjzYZVr3sWS2XKlG80mZ4rr4drk-5dzj4vcDo_areLst3m6LLxenf4P9-n-aFp8g8IJ0</recordid><startdate>20210806</startdate><enddate>20210806</enddate><creator>Li, Yajuan</creator><creator>Tan, Zhi</creator><creator>Zhang, Yaohua</creator><creator>Zhang, Zhao</creator><creator>Hu, Qingsong</creator><creator>Liang, 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noncoding RNA modulator potentiates phenylalanine metabolism in mice</title><author>Li, Yajuan ; Tan, Zhi ; Zhang, Yaohua ; Zhang, Zhao ; Hu, Qingsong ; Liang, Ke ; Jun, Yao ; Ye, Youqiong ; Li, Yi-Chuan ; Li, Chunlai ; Liao, Lan ; Xu, Jianming ; Xing, Zhen ; Pan, Yinghong ; Chatterjee, Sujash S ; Nguyen, Tina K ; Hsiao, Heidi ; Egranov, Sergey D ; Putluri, Nagireddy ; Coarfa, Cristian ; Hawke, David H ; Gunaratne, Preethi H ; Tsai, Kuang-Lei ; Han, Leng ; Hung, Mien-Chie ; Calin, George A ; Namour, Fares ; Guéant, Jean-Louis ; Muntau, Ania C ; Blau, Nenad ; Sutton, V Reid ; Schiff, Manuel ; Feillet, François ; Zhang, Shuxing ; Lin, Chunru ; Yang, Liuqing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-1a498da1ae31a51053eedd78e57ea83c4d54d49ac282fa34de51e727525b42473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acetylgalactosamine</topic><topic>Animal models</topic><topic>Animals</topic><topic>Biopterins - analogs & derivatives</topic><topic>Biopterins - metabolism</topic><topic>Biopterins - therapeutic use</topic><topic>Cell differentiation</topic><topic>Depletion</topic><topic>Diet</topic><topic>Disease Models, Animal</topic><topic>Enzymatic activity</topic><topic>Female</topic><topic>Growth rate</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Hydroxylase</topic><topic>Liver</topic><topic>Liver - embryology</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mimicry</topic><topic>Mutation</topic><topic>Nucleic Acid Conformation</topic><topic>Nutrition therapy</topic><topic>Patients</topic><topic>Phenotypes</topic><topic>Phenylalanine</topic><topic>Phenylalanine - administration & dosage</topic><topic>Phenylalanine - metabolism</topic><topic>Phenylalanine 4-monooxygenase</topic><topic>Phenylalanine Hydroxylase - deficiency</topic><topic>Phenylalanine Hydroxylase - genetics</topic><topic>Phenylalanine Hydroxylase - metabolism</topic><topic>Phenylketonuria</topic><topic>Phenylketonurias - drug therapy</topic><topic>Phenylketonurias - genetics</topic><topic>Phenylketonurias - metabolism</topic><topic>Pigmentation</topic><topic>Pluripotency</topic><topic>Protein Binding</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>RNA, Long Noncoding - chemistry</topic><topic>RNA, Long Noncoding - genetics</topic><topic>RNA, Long Noncoding - metabolism</topic><topic>RNA, Long Noncoding - therapeutic use</topic><topic>Seizures</topic><topic>Signs and symptoms</topic><topic>Stem cells</topic><topic>Substrates</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Yajuan</creatorcontrib><creatorcontrib>Tan, Zhi</creatorcontrib><creatorcontrib>Zhang, Yaohua</creatorcontrib><creatorcontrib>Zhang, 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Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Yajuan</au><au>Tan, Zhi</au><au>Zhang, Yaohua</au><au>Zhang, Zhao</au><au>Hu, Qingsong</au><au>Liang, Ke</au><au>Jun, Yao</au><au>Ye, Youqiong</au><au>Li, Yi-Chuan</au><au>Li, Chunlai</au><au>Liao, Lan</au><au>Xu, Jianming</au><au>Xing, Zhen</au><au>Pan, Yinghong</au><au>Chatterjee, Sujash S</au><au>Nguyen, Tina K</au><au>Hsiao, Heidi</au><au>Egranov, Sergey D</au><au>Putluri, Nagireddy</au><au>Coarfa, Cristian</au><au>Hawke, David H</au><au>Gunaratne, Preethi H</au><au>Tsai, Kuang-Lei</au><au>Han, Leng</au><au>Hung, Mien-Chie</au><au>Calin, George A</au><au>Namour, Fares</au><au>Guéant, Jean-Louis</au><au>Muntau, Ania C</au><au>Blau, Nenad</au><au>Sutton, V Reid</au><au>Schiff, Manuel</au><au>Feillet, François</au><au>Zhang, Shuxing</au><au>Lin, Chunru</au><au>Yang, Liuqing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A noncoding RNA modulator potentiates phenylalanine metabolism in mice</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2021-08-06</date><risdate>2021</risdate><volume>373</volume><issue>6555</issue><spage>662</spage><epage>673</epage><pages>662-673</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA
and human
associate with phenylalanine hydroxylase (PAH).
-knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU.
depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell-differentiated hepatocytes. Mechanistically,
modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc-
mimics reduced excessive Phe in
and
mice and improved the Phe tolerance of these mice.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>34353949</pmid><doi>10.1126/science.aba4991</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-2900-8378</orcidid><orcidid>https://orcid.org/0000-0003-4317-4740</orcidid><orcidid>https://orcid.org/0000-0002-6450-8554</orcidid><orcidid>https://orcid.org/0000-0002-7380-2640</orcidid><orcidid>https://orcid.org/0000-0001-8332-4710</orcidid><orcidid>https://orcid.org/0000-0001-7334-1787</orcidid><orcidid>https://orcid.org/0000-0001-8272-232X</orcidid><orcidid>https://orcid.org/0000-0002-8208-9162</orcidid><orcidid>https://orcid.org/0000-0003-1897-9889</orcidid><orcidid>https://orcid.org/0000-0003-1895-0285</orcidid><orcidid>https://orcid.org/0000-0002-9267-4701</orcidid><orcidid>https://orcid.org/0000-0002-6102-7843</orcidid><orcidid>https://orcid.org/0000-0002-1795-1051</orcidid><orcidid>https://orcid.org/0000-0002-8717-469X</orcidid><orcidid>https://orcid.org/0000-0003-2328-6956</orcidid><orcidid>https://orcid.org/0000-0002-3757-8469</orcidid><orcidid>https://orcid.org/0000-0002-6518-474X</orcidid><orcidid>https://orcid.org/0000-0003-4488-7400</orcidid><orcidid>https://orcid.org/0000-0002-9741-591X</orcidid><orcidid>https://orcid.org/0000-0002-5428-4219</orcidid><orcidid>https://orcid.org/0000-0001-8994-649X</orcidid><orcidid>https://orcid.org/0000-0002-6473-8229</orcidid><orcidid>https://orcid.org/0000-0003-1418-3576</orcidid><orcidid>https://orcid.org/0000-0002-6478-8752</orcidid><orcidid>https://orcid.org/0000-0002-4183-4939</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2021-08, Vol.373 (6555), p.662-673 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9714245 |
| source | MEDLINE; American Association for the Advancement of Science |
| subjects | Acetylgalactosamine Animal models Animals Biopterins - analogs & derivatives Biopterins - metabolism Biopterins - therapeutic use Cell differentiation Depletion Diet Disease Models, Animal Enzymatic activity Female Growth rate Hepatocytes Hepatocytes - metabolism Humans Hydroxylase Liver Liver - embryology Liver - metabolism Male Metabolic disorders Metabolism Mice Mice, Knockout Mimicry Mutation Nucleic Acid Conformation Nutrition therapy Patients Phenotypes Phenylalanine Phenylalanine - administration & dosage Phenylalanine - metabolism Phenylalanine 4-monooxygenase Phenylalanine Hydroxylase - deficiency Phenylalanine Hydroxylase - genetics Phenylalanine Hydroxylase - metabolism Phenylketonuria Phenylketonurias - drug therapy Phenylketonurias - genetics Phenylketonurias - metabolism Pigmentation Pluripotency Protein Binding Ribonucleic acid RNA RNA, Long Noncoding - chemistry RNA, Long Noncoding - genetics RNA, Long Noncoding - metabolism RNA, Long Noncoding - therapeutic use Seizures Signs and symptoms Stem cells Substrates |
| title | A noncoding RNA modulator potentiates phenylalanine metabolism in mice |
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