Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia
Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and anot...
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| Veröffentlicht in: | Science advances 2019-09, Vol.5 (9), p.eaau4139-eaau4139 |
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| creator | Doostparast Torshizi, Abolfazl Armoskus, Chris Zhang, Hanwen Forrest, Marc P Zhang, Siwei Souaiaia, Tade Evgrafov, Oleg V Knowles, James A Duan, Jubao Wang, Kai |
| description | Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified
as a top candidate MR that may be dysregulated in SCZ. We validated
as a MR through enrichment analysis of
-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted
targets by knocking down
in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed
gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that
may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment. |
| doi_str_mv | 10.1126/sciadv.aau4139 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6739105</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2293981930</sourcerecordid><originalsourceid>FETCH-LOGICAL-c456t-e3b87c1e907a5a760523d37ee8fbbbfce26befb48d965319a2b0f6e81358bc703</originalsourceid><addsrcrecordid>eNpVkc1LAzEQxYMoKurVo-TopTXZbLKbiyD1EwQveo6T7KyNbpOa7Fb0r7elVfQ0w8ybNw9-hBxzNua8UGfZeWgWY4Ch5EJvkf1CVHJUyLLe_tPvkaOcXxljvFRKcr1L9gSXQjIu98nzJboYFrEbeh8DjS3tE4Tskp-vBtDRgP1HTG-Z-gZD71uPmT5OrksKmQKdQe4x0YQvQwd9TNQHmt3Uf8X5NGHwcEh2WugyHm3qAXm6vnqc3I7uH27uJhf3I1dK1Y9Q2LpyHDWrQEKlmCxEIyrEurXWtg4LZbG1Zd1oJQXXUFjWKqy5kLV1FRMH5HztOx_sDBu3zJqgM_PkZ5A-TQRv_m-Cn5qXuDCqEpozuTQ43Rik-D5g7s3MZ4ddBwHjkE1RaKFrrsXq13gtdSnmnLD9fcOZWZExazJmQ2Z5cPI33K_8h4P4Bgemjyg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2293981930</pqid></control><display><type>article</type><title>Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>PubMed Central</source><creator>Doostparast Torshizi, Abolfazl ; Armoskus, Chris ; Zhang, Hanwen ; Forrest, Marc P ; Zhang, Siwei ; Souaiaia, Tade ; Evgrafov, Oleg V ; Knowles, James A ; Duan, Jubao ; Wang, Kai</creator><creatorcontrib>Doostparast Torshizi, Abolfazl ; Armoskus, Chris ; Zhang, Hanwen ; Forrest, Marc P ; Zhang, Siwei ; Souaiaia, Tade ; Evgrafov, Oleg V ; Knowles, James A ; Duan, Jubao ; Wang, Kai</creatorcontrib><description>Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified
as a top candidate MR that may be dysregulated in SCZ. We validated
as a MR through enrichment analysis of
-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted
targets by knocking down
in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed
gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that
may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.aau4139</identifier><identifier>PMID: 31535015</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Adult ; Case-Control Studies ; Cells, Cultured ; Diseases and Disorders ; Gene Regulatory Networks ; Genetic Predisposition to Disease ; Humans ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - pathology ; Male ; Neural Stem Cells - metabolism ; Neural Stem Cells - pathology ; Neuroepithelial Cells - metabolism ; Neuroepithelial Cells - pathology ; Neurons - metabolism ; Neurons - pathology ; Olfactory Mucosa - metabolism ; Olfactory Mucosa - pathology ; Prefrontal Cortex - metabolism ; Prefrontal Cortex - pathology ; Schizophrenia - genetics ; Schizophrenia - pathology ; SciAdv r-articles ; Systems Biology ; Transcription Factor 4 - genetics ; Transcription Factor 4 - metabolism</subject><ispartof>Science advances, 2019-09, Vol.5 (9), p.eaau4139-eaau4139</ispartof><rights>Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). 2019 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c456t-e3b87c1e907a5a760523d37ee8fbbbfce26befb48d965319a2b0f6e81358bc703</citedby><cites>FETCH-LOGICAL-c456t-e3b87c1e907a5a760523d37ee8fbbbfce26befb48d965319a2b0f6e81358bc703</cites><orcidid>0000-0002-9280-7850 ; 0000-0002-3307-5741 ; 0000-0002-5585-982X ; 0000-0001-5837-0600 ; 0000-0002-3327-699X ; 0000-0002-1646-063X ; 0000-0002-7215-3220</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739105/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6739105/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31535015$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Doostparast Torshizi, Abolfazl</creatorcontrib><creatorcontrib>Armoskus, Chris</creatorcontrib><creatorcontrib>Zhang, Hanwen</creatorcontrib><creatorcontrib>Forrest, Marc P</creatorcontrib><creatorcontrib>Zhang, Siwei</creatorcontrib><creatorcontrib>Souaiaia, Tade</creatorcontrib><creatorcontrib>Evgrafov, Oleg V</creatorcontrib><creatorcontrib>Knowles, James A</creatorcontrib><creatorcontrib>Duan, Jubao</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><title>Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified
as a top candidate MR that may be dysregulated in SCZ. We validated
as a MR through enrichment analysis of
-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted
targets by knocking down
in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed
gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that
may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.</description><subject>Adult</subject><subject>Case-Control Studies</subject><subject>Cells, Cultured</subject><subject>Diseases and Disorders</subject><subject>Gene Regulatory Networks</subject><subject>Genetic Predisposition to Disease</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Induced Pluripotent Stem Cells - pathology</subject><subject>Male</subject><subject>Neural Stem Cells - metabolism</subject><subject>Neural Stem Cells - pathology</subject><subject>Neuroepithelial Cells - metabolism</subject><subject>Neuroepithelial Cells - pathology</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Olfactory Mucosa - metabolism</subject><subject>Olfactory Mucosa - pathology</subject><subject>Prefrontal Cortex - metabolism</subject><subject>Prefrontal Cortex - pathology</subject><subject>Schizophrenia - genetics</subject><subject>Schizophrenia - pathology</subject><subject>SciAdv r-articles</subject><subject>Systems Biology</subject><subject>Transcription Factor 4 - genetics</subject><subject>Transcription Factor 4 - metabolism</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1LAzEQxYMoKurVo-TopTXZbLKbiyD1EwQveo6T7KyNbpOa7Fb0r7elVfQ0w8ybNw9-hBxzNua8UGfZeWgWY4Ch5EJvkf1CVHJUyLLe_tPvkaOcXxljvFRKcr1L9gSXQjIu98nzJboYFrEbeh8DjS3tE4Tskp-vBtDRgP1HTG-Z-gZD71uPmT5OrksKmQKdQe4x0YQvQwd9TNQHmt3Uf8X5NGHwcEh2WugyHm3qAXm6vnqc3I7uH27uJhf3I1dK1Y9Q2LpyHDWrQEKlmCxEIyrEurXWtg4LZbG1Zd1oJQXXUFjWKqy5kLV1FRMH5HztOx_sDBu3zJqgM_PkZ5A-TQRv_m-Cn5qXuDCqEpozuTQ43Rik-D5g7s3MZ4ddBwHjkE1RaKFrrsXq13gtdSnmnLD9fcOZWZExazJmQ2Z5cPI33K_8h4P4Bgemjyg</recordid><startdate>20190901</startdate><enddate>20190901</enddate><creator>Doostparast Torshizi, Abolfazl</creator><creator>Armoskus, Chris</creator><creator>Zhang, Hanwen</creator><creator>Forrest, Marc P</creator><creator>Zhang, Siwei</creator><creator>Souaiaia, Tade</creator><creator>Evgrafov, Oleg V</creator><creator>Knowles, James A</creator><creator>Duan, Jubao</creator><creator>Wang, Kai</creator><general>American Association for the Advancement of Science</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9280-7850</orcidid><orcidid>https://orcid.org/0000-0002-3307-5741</orcidid><orcidid>https://orcid.org/0000-0002-5585-982X</orcidid><orcidid>https://orcid.org/0000-0001-5837-0600</orcidid><orcidid>https://orcid.org/0000-0002-3327-699X</orcidid><orcidid>https://orcid.org/0000-0002-1646-063X</orcidid><orcidid>https://orcid.org/0000-0002-7215-3220</orcidid></search><sort><creationdate>20190901</creationdate><title>Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia</title><author>Doostparast Torshizi, Abolfazl ; Armoskus, Chris ; Zhang, Hanwen ; Forrest, Marc P ; Zhang, Siwei ; Souaiaia, Tade ; Evgrafov, Oleg V ; Knowles, James A ; Duan, Jubao ; Wang, Kai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c456t-e3b87c1e907a5a760523d37ee8fbbbfce26befb48d965319a2b0f6e81358bc703</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Adult</topic><topic>Case-Control Studies</topic><topic>Cells, Cultured</topic><topic>Diseases and Disorders</topic><topic>Gene Regulatory Networks</topic><topic>Genetic Predisposition to Disease</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - metabolism</topic><topic>Induced Pluripotent Stem Cells - pathology</topic><topic>Male</topic><topic>Neural Stem Cells - metabolism</topic><topic>Neural Stem Cells - pathology</topic><topic>Neuroepithelial Cells - metabolism</topic><topic>Neuroepithelial Cells - pathology</topic><topic>Neurons - metabolism</topic><topic>Neurons - pathology</topic><topic>Olfactory Mucosa - metabolism</topic><topic>Olfactory Mucosa - pathology</topic><topic>Prefrontal Cortex - metabolism</topic><topic>Prefrontal Cortex - pathology</topic><topic>Schizophrenia - genetics</topic><topic>Schizophrenia - pathology</topic><topic>SciAdv r-articles</topic><topic>Systems Biology</topic><topic>Transcription Factor 4 - genetics</topic><topic>Transcription Factor 4 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Doostparast Torshizi, Abolfazl</creatorcontrib><creatorcontrib>Armoskus, Chris</creatorcontrib><creatorcontrib>Zhang, Hanwen</creatorcontrib><creatorcontrib>Forrest, Marc P</creatorcontrib><creatorcontrib>Zhang, Siwei</creatorcontrib><creatorcontrib>Souaiaia, Tade</creatorcontrib><creatorcontrib>Evgrafov, Oleg V</creatorcontrib><creatorcontrib>Knowles, James A</creatorcontrib><creatorcontrib>Duan, Jubao</creatorcontrib><creatorcontrib>Wang, Kai</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science advances</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Doostparast Torshizi, Abolfazl</au><au>Armoskus, Chris</au><au>Zhang, Hanwen</au><au>Forrest, Marc P</au><au>Zhang, Siwei</au><au>Souaiaia, Tade</au><au>Evgrafov, Oleg V</au><au>Knowles, James A</au><au>Duan, Jubao</au><au>Wang, Kai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2019-09-01</date><risdate>2019</risdate><volume>5</volume><issue>9</issue><spage>eaau4139</spage><epage>eaau4139</epage><pages>eaau4139-eaau4139</pages><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Applying tissue-specific deconvolution of transcriptional networks to identify their master regulators (MRs) in neuropsychiatric disorders has been largely unexplored. Here, using two schizophrenia (SCZ) case-control RNA-seq datasets, one on postmortem dorsolateral prefrontal cortex (DLPFC) and another on cultured olfactory neuroepithelium, we deconvolved the transcriptional networks and identified
as a top candidate MR that may be dysregulated in SCZ. We validated
as a MR through enrichment analysis of
-binding sites in induced pluripotent stem cell (hiPSC)-derived neurons and in neuroblastoma cells. We further validated the predicted
targets by knocking down
in hiPSC-derived neural progenitor cells (NPCs) and glutamatergic neurons (Glut_Ns). The perturbed
gene network in NPCs was more enriched for pathways involved in neuronal activity and SCZ-associated risk genes, compared to Glut_Ns. Our results suggest that
may serve as a MR of a gene network dysregulated in SCZ at early stages of neurodevelopment.</abstract><cop>United States</cop><pub>American Association for the Advancement of Science</pub><pmid>31535015</pmid><doi>10.1126/sciadv.aau4139</doi><orcidid>https://orcid.org/0000-0002-9280-7850</orcidid><orcidid>https://orcid.org/0000-0002-3307-5741</orcidid><orcidid>https://orcid.org/0000-0002-5585-982X</orcidid><orcidid>https://orcid.org/0000-0001-5837-0600</orcidid><orcidid>https://orcid.org/0000-0002-3327-699X</orcidid><orcidid>https://orcid.org/0000-0002-1646-063X</orcidid><orcidid>https://orcid.org/0000-0002-7215-3220</orcidid><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | Adult Case-Control Studies Cells, Cultured Diseases and Disorders Gene Regulatory Networks Genetic Predisposition to Disease Humans Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Male Neural Stem Cells - metabolism Neural Stem Cells - pathology Neuroepithelial Cells - metabolism Neuroepithelial Cells - pathology Neurons - metabolism Neurons - pathology Olfactory Mucosa - metabolism Olfactory Mucosa - pathology Prefrontal Cortex - metabolism Prefrontal Cortex - pathology Schizophrenia - genetics Schizophrenia - pathology SciAdv r-articles Systems Biology Transcription Factor 4 - genetics Transcription Factor 4 - metabolism |
| title | Deconvolution of transcriptional networks identifies TCF4 as a master regulator in schizophrenia |
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