RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma
Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a pro...
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| Veröffentlicht in: | The Journal of clinical investigation 2024-06, Vol.134 (11), p.1-17 |
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| creator | Song, Xiao Tiek, Deanna Miki, Shunichiro Huang, Tianzhi Lu, Minghui Goenka, Anshika Iglesia, Rebeca Yu, Xiaozhou Wu, Runxin Walker, Maya Zeng, Chang Shah, Hardik Weng, Shao Huan Samuel Huff, Allen Zhang, Wei Koga, Tomoyuki Hubert, Christopher Horbinski, Craig M Furnari, Frank B Hu, Bo Cheng, Shi-Yuan |
| description | Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas. |
| doi_str_mv | 10.1172/JCI173789 |
| format | Article |
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However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.</description><identifier>ISSN: 1558-8238</identifier><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI173789</identifier><identifier>PMID: 38662454</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adult ; Alternative Splicing ; Analysis ; Animals ; Brain cancer ; Brain Neoplasms - genetics ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Brain Neoplasms - therapy ; Cell Line, Tumor ; Datasets ; Development and progression ; Genetic aspects ; Glioma ; Glioma - genetics ; Glioma - metabolism ; Glioma - pathology ; Glioma - therapy ; Glioma cells ; Gliomas ; Heterogeneous-Nuclear Ribonucleoproteins - genetics ; Heterogeneous-Nuclear Ribonucleoproteins - metabolism ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Lipid metabolism ; Malignancy ; Medical prognosis ; Membrane Proteins - genetics ; Membrane Proteins - metabolism ; Mice ; Mutation ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Nervous system ; Neurons ; Neurophysiology ; Physiological aspects ; Polypyrimidine Tract-Binding Protein - genetics ; Polypyrimidine Tract-Binding Protein - metabolism ; Protein binding ; Proteins ; Ribonucleic acid ; Risk factors ; RNA ; RNA sequencing ; RNA splicing ; RNA-binding protein ; Stem cells ; Therapeutic targets ; Tumors</subject><ispartof>The Journal of clinical investigation, 2024-06, Vol.134 (11), p.1-17</ispartof><rights>COPYRIGHT 2024 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jun 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c512t-f940d4ec9c42a5aa7be536845b704fd50cc8ad5b959e66d098746d83a3cecb8d3</cites><orcidid>0000-0001-8408-5686 ; 0000-0001-8340-9992 ; 0000-0003-0875-263X ; 0000-0002-2881-7691</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38662454$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Xiao</creatorcontrib><creatorcontrib>Tiek, Deanna</creatorcontrib><creatorcontrib>Miki, Shunichiro</creatorcontrib><creatorcontrib>Huang, Tianzhi</creatorcontrib><creatorcontrib>Lu, Minghui</creatorcontrib><creatorcontrib>Goenka, Anshika</creatorcontrib><creatorcontrib>Iglesia, Rebeca</creatorcontrib><creatorcontrib>Yu, Xiaozhou</creatorcontrib><creatorcontrib>Wu, Runxin</creatorcontrib><creatorcontrib>Walker, Maya</creatorcontrib><creatorcontrib>Zeng, Chang</creatorcontrib><creatorcontrib>Shah, Hardik</creatorcontrib><creatorcontrib>Weng, Shao Huan Samuel</creatorcontrib><creatorcontrib>Huff, Allen</creatorcontrib><creatorcontrib>Zhang, Wei</creatorcontrib><creatorcontrib>Koga, Tomoyuki</creatorcontrib><creatorcontrib>Hubert, Christopher</creatorcontrib><creatorcontrib>Horbinski, Craig M</creatorcontrib><creatorcontrib>Furnari, Frank B</creatorcontrib><creatorcontrib>Hu, Bo</creatorcontrib><creatorcontrib>Cheng, Shi-Yuan</creatorcontrib><title>RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. Overall, our data highlights the role of AS in affecting glioma malignancy and heterogeneity and its potential as a therapeutic vulnerability for treating adult gliomas.</description><subject>Adult</subject><subject>Alternative Splicing</subject><subject>Analysis</subject><subject>Animals</subject><subject>Brain cancer</subject><subject>Brain Neoplasms - genetics</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - therapy</subject><subject>Cell Line, Tumor</subject><subject>Datasets</subject><subject>Development and progression</subject><subject>Genetic aspects</subject><subject>Glioma</subject><subject>Glioma - genetics</subject><subject>Glioma - metabolism</subject><subject>Glioma - pathology</subject><subject>Glioma - therapy</subject><subject>Glioma cells</subject><subject>Gliomas</subject><subject>Heterogeneous-Nuclear Ribonucleoproteins - genetics</subject><subject>Heterogeneous-Nuclear Ribonucleoproteins - metabolism</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Lipid metabolism</subject><subject>Malignancy</subject><subject>Medical prognosis</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mutation</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Nervous system</subject><subject>Neurons</subject><subject>Neurophysiology</subject><subject>Physiological aspects</subject><subject>Polypyrimidine Tract-Binding Protein - genetics</subject><subject>Polypyrimidine Tract-Binding Protein - metabolism</subject><subject>Protein binding</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>Risk factors</subject><subject>RNA</subject><subject>RNA sequencing</subject><subject>RNA splicing</subject><subject>RNA-binding protein</subject><subject>Stem cells</subject><subject>Therapeutic targets</subject><subject>Tumors</subject><issn>1558-8238</issn><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqN0s1u1DAQAOAIgWgpHHgBZAkJlUOKndixfVytKCyqqFR-rpFjT7KunDi1HUTfHq8opYv2gHyYkf15DjNTFC8JPiOEV-8-rTeE11zIR8UxYUyUoqrF4wf5UfEsxmuMCaWMPi2OatE0VU6PC3v1eYXi7Ky204DUpNxttBEZ0HbeQthlP8D5eYQpKYe2FoIKOoeYsUEhvyoXUcpWzbAkq1FSYYAUkZ2QMotLaHDWj-p58aTPFF7cxZPi2_n7r-uP5cXlh816dVFqRqpU9pJiQ0FLTSvFlOIdsLoRlHUc094wrLVQhnWSSWgag6XgtDGiVrUG3QlTnxSnv-vOwd8sEFM72qjBOTWBX2JbY8olzTV5pq__odd-CbkHO9VwKogUzV81KAetnXqfgtK7ou2KSy4wF4RkVR5QA0y5Mc5P0Nt8vefPDvh8DIxWH_zwdu9DNgl-pkEtMbabL1f_by-_79s3D-w2jzNto3d5lH6KB4vq4GMM0LdzsKMKty3B7W4P2_s9zPbVXWeXbgRzL_8sXv0LrUHUXQ</recordid><startdate>20240601</startdate><enddate>20240601</enddate><creator>Song, Xiao</creator><creator>Tiek, Deanna</creator><creator>Miki, Shunichiro</creator><creator>Huang, Tianzhi</creator><creator>Lu, Minghui</creator><creator>Goenka, Anshika</creator><creator>Iglesia, Rebeca</creator><creator>Yu, Xiaozhou</creator><creator>Wu, Runxin</creator><creator>Walker, Maya</creator><creator>Zeng, Chang</creator><creator>Shah, Hardik</creator><creator>Weng, Shao Huan Samuel</creator><creator>Huff, Allen</creator><creator>Zhang, Wei</creator><creator>Koga, Tomoyuki</creator><creator>Hubert, Christopher</creator><creator>Horbinski, Craig M</creator><creator>Furnari, Frank B</creator><creator>Hu, Bo</creator><creator>Cheng, Shi-Yuan</creator><general>American Society for Clinical Investigation</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8408-5686</orcidid><orcidid>https://orcid.org/0000-0001-8340-9992</orcidid><orcidid>https://orcid.org/0000-0003-0875-263X</orcidid><orcidid>https://orcid.org/0000-0002-2881-7691</orcidid></search><sort><creationdate>20240601</creationdate><title>RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma</title><author>Song, Xiao ; Tiek, Deanna ; Miki, Shunichiro ; Huang, Tianzhi ; Lu, Minghui ; Goenka, Anshika ; Iglesia, Rebeca ; Yu, Xiaozhou ; Wu, Runxin ; Walker, Maya ; Zeng, Chang ; Shah, Hardik ; Weng, Shao Huan Samuel ; Huff, Allen ; Zhang, Wei ; Koga, Tomoyuki ; Hubert, Christopher ; Horbinski, Craig M ; Furnari, Frank B ; Hu, Bo ; Cheng, Shi-Yuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c512t-f940d4ec9c42a5aa7be536845b704fd50cc8ad5b959e66d098746d83a3cecb8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Adult</topic><topic>Alternative Splicing</topic><topic>Analysis</topic><topic>Animals</topic><topic>Brain cancer</topic><topic>Brain Neoplasms - genetics</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain Neoplasms - therapy</topic><topic>Cell Line, Tumor</topic><topic>Datasets</topic><topic>Development and progression</topic><topic>Genetic aspects</topic><topic>Glioma</topic><topic>Glioma - genetics</topic><topic>Glioma - metabolism</topic><topic>Glioma - pathology</topic><topic>Glioma - therapy</topic><topic>Glioma cells</topic><topic>Gliomas</topic><topic>Heterogeneous-Nuclear Ribonucleoproteins - genetics</topic><topic>Heterogeneous-Nuclear Ribonucleoproteins - metabolism</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Lipid metabolism</topic><topic>Malignancy</topic><topic>Medical prognosis</topic><topic>Membrane Proteins - genetics</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice</topic><topic>Mutation</topic><topic>Neoplasm Proteins - genetics</topic><topic>Neoplasm Proteins - metabolism</topic><topic>Nervous system</topic><topic>Neurons</topic><topic>Neurophysiology</topic><topic>Physiological aspects</topic><topic>Polypyrimidine Tract-Binding Protein - 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Academic</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Xiao</au><au>Tiek, Deanna</au><au>Miki, Shunichiro</au><au>Huang, Tianzhi</au><au>Lu, Minghui</au><au>Goenka, Anshika</au><au>Iglesia, Rebeca</au><au>Yu, Xiaozhou</au><au>Wu, Runxin</au><au>Walker, Maya</au><au>Zeng, Chang</au><au>Shah, Hardik</au><au>Weng, Shao Huan Samuel</au><au>Huff, Allen</au><au>Zhang, Wei</au><au>Koga, Tomoyuki</au><au>Hubert, Christopher</au><au>Horbinski, Craig M</au><au>Furnari, Frank B</au><au>Hu, Bo</au><au>Cheng, Shi-Yuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2024-06-01</date><risdate>2024</risdate><volume>134</volume><issue>11</issue><spage>1</spage><epage>17</epage><pages>1-17</pages><issn>1558-8238</issn><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Widespread alterations in RNA alternative splicing (AS) have been identified in adult gliomas. However, their regulatory mechanism, biological significance, and therapeutic potential remain largely elusive. Here, using a computational approach with both bulk and single-cell RNA-Seq, we uncover a prognostic AS signature linked with neural developmental hierarchies. Using advanced iPSC glioma models driven by glioma driver mutations, we show that this AS signature could be enhanced by EGFRvIII and inhibited by in situ IDH1 mutation. Functional validations of 2 isoform switching events in CERS5 and MPZL1 show regulations of sphingolipid metabolism and SHP2 signaling, respectively. Analysis of upstream RNA binding proteins reveals PTBP1 as a key regulator of the AS signature where targeting of PTBP1 suppresses tumor growth and promotes the expression of a neuron marker TUJ1 in glioma stem-like cells. 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| subjects | Adult Alternative Splicing Analysis Animals Brain cancer Brain Neoplasms - genetics Brain Neoplasms - metabolism Brain Neoplasms - pathology Brain Neoplasms - therapy Cell Line, Tumor Datasets Development and progression Genetic aspects Glioma Glioma - genetics Glioma - metabolism Glioma - pathology Glioma - therapy Glioma cells Gliomas Heterogeneous-Nuclear Ribonucleoproteins - genetics Heterogeneous-Nuclear Ribonucleoproteins - metabolism Humans Induced Pluripotent Stem Cells - metabolism Lipid metabolism Malignancy Medical prognosis Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mutation Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Nervous system Neurons Neurophysiology Physiological aspects Polypyrimidine Tract-Binding Protein - genetics Polypyrimidine Tract-Binding Protein - metabolism Protein binding Proteins Ribonucleic acid Risk factors RNA RNA sequencing RNA splicing RNA-binding protein Stem cells Therapeutic targets Tumors |
| title | RNA splicing analysis deciphers developmental hierarchies and reveals therapeutic targets in adult glioma |
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