MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice
Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (...
Gespeichert in:
| Veröffentlicht in: | Molecular psychiatry 2018-01, Vol.23 (1), p.123-132 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 132 |
|---|---|
| container_issue | 1 |
| container_start_page | 123 |
| container_title | Molecular psychiatry |
| container_volume | 23 |
| creator | Mitchell, A C Javidfar, B Pothula, V Ibi, D Shen, E Y Peter, C J Bicks, L K Fehr, T Jiang, Y Brennand, K J Neve, R L Gonzalez-Maeso, J Akbarian, S |
| description | Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (
MEF2C
) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within
cis
-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term
Mef2c
upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging
in vivo
by
Mef2c-Dam
adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders. |
| doi_str_mv | 10.1038/mp.2016.254 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5966823</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A521121936</galeid><sourcerecordid>A521121936</sourcerecordid><originalsourceid>FETCH-LOGICAL-c513t-34da793a9a3ee58d0b5bb51738fa36334753c8902bd1cdf5aa9a089308ca058d3</originalsourceid><addsrcrecordid>eNptkk1v1DAQhi0EomXhxB1Z4oIEWfwRJ86lUrVqAamIC5wtx5kkLhs72E4R_AR-Nd7dtrSo8sEezzPv-LUGoZeUrCnh8v00rxmh1ZqJ8hE6pmVdFULU8nE-c9EUJZXlEXoW4yUhu6R4io6YpFTUJTtGfz6fnbMNTkG7aIKdk_UO99okH7CNWMfojdUJOvzTphGnEfAADpI1WLsOw2xvwmDjd6yDGW0Ck5YA2Pc45vC3n8cAzup9hZ3m4K8gYuMHZ_ftrMOTNfAcPen1NsKL632Fvp2ffd18LC6-fPi0Ob0ojKA8FbzsdN1w3WgOIGRHWtG2gtZc9ppXnJe14EY2hLUdNV0vdCaJbDiRRpPM8xU6OejOSztBZ8Bl91s1Bzvp8Et5bdX9jLOjGvyVEk1VScazwJtrgeB_LBCTmmw0sN1qB36JisqKVpSWoszo6__QS78El-0p2khe1YI29T9q0FtQ1vU-9zU7UXUqGKWMNtnZCq0foPLqIH-fd9DbfH-v4O2hwAQfY4D-1iMlajc6aprVbnQU2z_11d1vuWVvZiUD7w5AzCk3QLjj5QG9v9U4zrk</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1983675197</pqid></control><display><type>article</type><title>MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice</title><source>MEDLINE</source><source>SpringerLink Journals</source><creator>Mitchell, A C ; Javidfar, B ; Pothula, V ; Ibi, D ; Shen, E Y ; Peter, C J ; Bicks, L K ; Fehr, T ; Jiang, Y ; Brennand, K J ; Neve, R L ; Gonzalez-Maeso, J ; Akbarian, S</creator><creatorcontrib>Mitchell, A C ; Javidfar, B ; Pothula, V ; Ibi, D ; Shen, E Y ; Peter, C J ; Bicks, L K ; Fehr, T ; Jiang, Y ; Brennand, K J ; Neve, R L ; Gonzalez-Maeso, J ; Akbarian, S</creatorcontrib><description>Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (
MEF2C
) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within
cis
-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term
Mef2c
upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging
in vivo
by
Mef2c-Dam
adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/mp.2016.254</identifier><identifier>PMID: 28115742</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>42 ; 42/44 ; 45/15 ; 631/337 ; 692/699/476/1799 ; Adenine ; Animals ; Behavioral Sciences ; Biological Psychology ; Brain - metabolism ; Brain - pathology ; Chromatin ; Chromatin Immunoprecipitation ; Cognition ; Cognition Disorders - etiology ; Cognition Disorders - metabolism ; Cognition Disorders - therapy ; Cognitive ability ; Computational Biology ; Disease Models, Animal ; Enrichment ; Epigenomics - methods ; Fusion protein ; Gene expression ; Gene Expression Regulation - genetics ; Gene mapping ; Genetic aspects ; Green Fluorescent Proteins - genetics ; Green Fluorescent Proteins - metabolism ; Heritability ; Histones - genetics ; Histones - metabolism ; Medicine ; Medicine & Public Health ; MEF2 Transcription Factors - genetics ; MEF2 Transcription Factors - metabolism ; Mental disorders ; Methyltransferase ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Tissue Proteins - metabolism ; Neural networks ; Neurons - metabolism ; Neurosciences ; Nucleosomes ; original-article ; Pattern recognition ; Pharmacotherapy ; Polymorphism, Single Nucleotide - genetics ; Prefrontal cortex ; Promoters ; Psychiatry ; Regulatory sequences ; Schizophrenia ; Schizophrenia - complications ; Schizophrenia - genetics ; Schizophrenia - pathology ; Short term memory ; Single-nucleotide polymorphism ; Transcription factors ; Transduction, Genetic</subject><ispartof>Molecular psychiatry, 2018-01, Vol.23 (1), p.123-132</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. 2018</rights><rights>COPYRIGHT 2018 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jan 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c513t-34da793a9a3ee58d0b5bb51738fa36334753c8902bd1cdf5aa9a089308ca058d3</citedby><cites>FETCH-LOGICAL-c513t-34da793a9a3ee58d0b5bb51738fa36334753c8902bd1cdf5aa9a089308ca058d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/mp.2016.254$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/mp.2016.254$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28115742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mitchell, A C</creatorcontrib><creatorcontrib>Javidfar, B</creatorcontrib><creatorcontrib>Pothula, V</creatorcontrib><creatorcontrib>Ibi, D</creatorcontrib><creatorcontrib>Shen, E Y</creatorcontrib><creatorcontrib>Peter, C J</creatorcontrib><creatorcontrib>Bicks, L K</creatorcontrib><creatorcontrib>Fehr, T</creatorcontrib><creatorcontrib>Jiang, Y</creatorcontrib><creatorcontrib>Brennand, K J</creatorcontrib><creatorcontrib>Neve, R L</creatorcontrib><creatorcontrib>Gonzalez-Maeso, J</creatorcontrib><creatorcontrib>Akbarian, S</creatorcontrib><title>MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><addtitle>Mol Psychiatry</addtitle><description>Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (
MEF2C
) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within
cis
-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term
Mef2c
upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging
in vivo
by
Mef2c-Dam
adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.</description><subject>42</subject><subject>42/44</subject><subject>45/15</subject><subject>631/337</subject><subject>692/699/476/1799</subject><subject>Adenine</subject><subject>Animals</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Brain - metabolism</subject><subject>Brain - pathology</subject><subject>Chromatin</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cognition</subject><subject>Cognition Disorders - etiology</subject><subject>Cognition Disorders - metabolism</subject><subject>Cognition Disorders - therapy</subject><subject>Cognitive ability</subject><subject>Computational Biology</subject><subject>Disease Models, Animal</subject><subject>Enrichment</subject><subject>Epigenomics - methods</subject><subject>Fusion protein</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - genetics</subject><subject>Gene mapping</subject><subject>Genetic aspects</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>Green Fluorescent Proteins - metabolism</subject><subject>Heritability</subject><subject>Histones - genetics</subject><subject>Histones - metabolism</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>MEF2 Transcription Factors - genetics</subject><subject>MEF2 Transcription Factors - metabolism</subject><subject>Mental disorders</subject><subject>Methyltransferase</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Nerve Tissue Proteins - metabolism</subject><subject>Neural networks</subject><subject>Neurons - metabolism</subject><subject>Neurosciences</subject><subject>Nucleosomes</subject><subject>original-article</subject><subject>Pattern recognition</subject><subject>Pharmacotherapy</subject><subject>Polymorphism, Single Nucleotide - genetics</subject><subject>Prefrontal cortex</subject><subject>Promoters</subject><subject>Psychiatry</subject><subject>Regulatory sequences</subject><subject>Schizophrenia</subject><subject>Schizophrenia - complications</subject><subject>Schizophrenia - genetics</subject><subject>Schizophrenia - pathology</subject><subject>Short term memory</subject><subject>Single-nucleotide polymorphism</subject><subject>Transcription factors</subject><subject>Transduction, Genetic</subject><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkk1v1DAQhi0EomXhxB1Z4oIEWfwRJ86lUrVqAamIC5wtx5kkLhs72E4R_AR-Nd7dtrSo8sEezzPv-LUGoZeUrCnh8v00rxmh1ZqJ8hE6pmVdFULU8nE-c9EUJZXlEXoW4yUhu6R4io6YpFTUJTtGfz6fnbMNTkG7aIKdk_UO99okH7CNWMfojdUJOvzTphGnEfAADpI1WLsOw2xvwmDjd6yDGW0Ck5YA2Pc45vC3n8cAzup9hZ3m4K8gYuMHZ_ftrMOTNfAcPen1NsKL632Fvp2ffd18LC6-fPi0Ob0ojKA8FbzsdN1w3WgOIGRHWtG2gtZc9ppXnJe14EY2hLUdNV0vdCaJbDiRRpPM8xU6OejOSztBZ8Bl91s1Bzvp8Et5bdX9jLOjGvyVEk1VScazwJtrgeB_LBCTmmw0sN1qB36JisqKVpSWoszo6__QS78El-0p2khe1YI29T9q0FtQ1vU-9zU7UXUqGKWMNtnZCq0foPLqIH-fd9DbfH-v4O2hwAQfY4D-1iMlajc6aprVbnQU2z_11d1vuWVvZiUD7w5AzCk3QLjj5QG9v9U4zrk</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Mitchell, A C</creator><creator>Javidfar, B</creator><creator>Pothula, V</creator><creator>Ibi, D</creator><creator>Shen, E Y</creator><creator>Peter, C J</creator><creator>Bicks, L K</creator><creator>Fehr, T</creator><creator>Jiang, Y</creator><creator>Brennand, K J</creator><creator>Neve, R L</creator><creator>Gonzalez-Maeso, J</creator><creator>Akbarian, S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</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>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>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>M7P</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180101</creationdate><title>MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice</title><author>Mitchell, A C ; Javidfar, B ; Pothula, V ; Ibi, D ; Shen, E Y ; Peter, C J ; Bicks, L K ; Fehr, T ; Jiang, Y ; Brennand, K J ; Neve, R L ; Gonzalez-Maeso, J ; Akbarian, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c513t-34da793a9a3ee58d0b5bb51738fa36334753c8902bd1cdf5aa9a089308ca058d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>42</topic><topic>42/44</topic><topic>45/15</topic><topic>631/337</topic><topic>692/699/476/1799</topic><topic>Adenine</topic><topic>Animals</topic><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Brain - metabolism</topic><topic>Brain - pathology</topic><topic>Chromatin</topic><topic>Chromatin Immunoprecipitation</topic><topic>Cognition</topic><topic>Cognition Disorders - etiology</topic><topic>Cognition Disorders - metabolism</topic><topic>Cognition Disorders - therapy</topic><topic>Cognitive ability</topic><topic>Computational Biology</topic><topic>Disease Models, Animal</topic><topic>Enrichment</topic><topic>Epigenomics - methods</topic><topic>Fusion protein</topic><topic>Gene expression</topic><topic>Gene Expression Regulation - genetics</topic><topic>Gene mapping</topic><topic>Genetic aspects</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>Green Fluorescent Proteins - metabolism</topic><topic>Heritability</topic><topic>Histones - genetics</topic><topic>Histones - metabolism</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>MEF2 Transcription Factors - genetics</topic><topic>MEF2 Transcription Factors - metabolism</topic><topic>Mental disorders</topic><topic>Methyltransferase</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Nerve Tissue Proteins - metabolism</topic><topic>Neural networks</topic><topic>Neurons - metabolism</topic><topic>Neurosciences</topic><topic>Nucleosomes</topic><topic>original-article</topic><topic>Pattern recognition</topic><topic>Pharmacotherapy</topic><topic>Polymorphism, Single Nucleotide - genetics</topic><topic>Prefrontal cortex</topic><topic>Promoters</topic><topic>Psychiatry</topic><topic>Regulatory sequences</topic><topic>Schizophrenia</topic><topic>Schizophrenia - complications</topic><topic>Schizophrenia - genetics</topic><topic>Schizophrenia - pathology</topic><topic>Short term memory</topic><topic>Single-nucleotide polymorphism</topic><topic>Transcription factors</topic><topic>Transduction, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mitchell, A C</creatorcontrib><creatorcontrib>Javidfar, B</creatorcontrib><creatorcontrib>Pothula, V</creatorcontrib><creatorcontrib>Ibi, D</creatorcontrib><creatorcontrib>Shen, E Y</creatorcontrib><creatorcontrib>Peter, C J</creatorcontrib><creatorcontrib>Bicks, L K</creatorcontrib><creatorcontrib>Fehr, T</creatorcontrib><creatorcontrib>Jiang, Y</creatorcontrib><creatorcontrib>Brennand, K J</creatorcontrib><creatorcontrib>Neve, R L</creatorcontrib><creatorcontrib>Gonzalez-Maeso, J</creatorcontrib><creatorcontrib>Akbarian, S</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular psychiatry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mitchell, A C</au><au>Javidfar, B</au><au>Pothula, V</au><au>Ibi, D</au><au>Shen, E Y</au><au>Peter, C J</au><au>Bicks, L K</au><au>Fehr, T</au><au>Jiang, Y</au><au>Brennand, K J</au><au>Neve, R L</au><au>Gonzalez-Maeso, J</au><au>Akbarian, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><addtitle>Mol Psychiatry</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>23</volume><issue>1</issue><spage>123</spage><epage>132</epage><pages>123-132</pages><issn>1359-4184</issn><issn>1476-5578</issn><eissn>1476-5578</eissn><abstract>Large-scale consortia mapping the genomic risk architectures of schizophrenia provide vast amounts of molecular information, with largely unexplored therapeutic potential. We harnessed publically available information from the Psychiatric Genomics Consortium, and report myocyte enhancer factor 2C (
MEF2C
) motif enrichment in sequences surrounding the top scoring single-nucleotide polymorphisms within risk loci contributing by individual small effect to disease heritability. Chromatin profiling at base-pair resolution in neuronal nucleosomes extracted from prefrontal cortex of 34 subjects, including 17 cases diagnosed with schizophrenia, revealed MEF2C motif enrichment within
cis
-regulatory sequences, including neuron-specific promoters and superenhancers, affected by histone H3K4 hypermethylation in disease cases. Vector-induced short- and long-term
Mef2c
upregulation in mouse prefrontal projection neurons consistently resulted in enhanced cognitive performance in working memory and object recognition paradigms at baseline and after psychotogenic drug challenge, in conjunction with remodeling of local connectivity. Neuronal genome tagging
in vivo
by
Mef2c-Dam
adenine methyltransferase fusion protein confirmed the link between cognitive enhancement and MEF2C occupancy at promoters harboring canonical and variant MEF2C motifs. The multilayered integrative approaches presented here provide a roadmap to uncover the therapeutic potential of transcriptional regulators for schizophrenia and related disorders.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28115742</pmid><doi>10.1038/mp.2016.254</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2018-01, Vol.23 (1), p.123-132 |
| issn | 1359-4184 1476-5578 1476-5578 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5966823 |
| source | MEDLINE; SpringerLink Journals |
| subjects | 42 42/44 45/15 631/337 692/699/476/1799 Adenine Animals Behavioral Sciences Biological Psychology Brain - metabolism Brain - pathology Chromatin Chromatin Immunoprecipitation Cognition Cognition Disorders - etiology Cognition Disorders - metabolism Cognition Disorders - therapy Cognitive ability Computational Biology Disease Models, Animal Enrichment Epigenomics - methods Fusion protein Gene expression Gene Expression Regulation - genetics Gene mapping Genetic aspects Green Fluorescent Proteins - genetics Green Fluorescent Proteins - metabolism Heritability Histones - genetics Histones - metabolism Medicine Medicine & Public Health MEF2 Transcription Factors - genetics MEF2 Transcription Factors - metabolism Mental disorders Methyltransferase Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins - metabolism Neural networks Neurons - metabolism Neurosciences Nucleosomes original-article Pattern recognition Pharmacotherapy Polymorphism, Single Nucleotide - genetics Prefrontal cortex Promoters Psychiatry Regulatory sequences Schizophrenia Schizophrenia - complications Schizophrenia - genetics Schizophrenia - pathology Short term memory Single-nucleotide polymorphism Transcription factors Transduction, Genetic |
| title | MEF2C transcription factor is associated with the genetic and epigenetic risk architecture of schizophrenia and improves cognition in mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-10T06%3A07%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=MEF2C%20transcription%20factor%20is%20associated%20with%20the%20genetic%20and%20epigenetic%20risk%20architecture%20of%20schizophrenia%20and%20improves%20cognition%20in%20mice&rft.jtitle=Molecular%20psychiatry&rft.au=Mitchell,%20A%20C&rft.date=2018-01-01&rft.volume=23&rft.issue=1&rft.spage=123&rft.epage=132&rft.pages=123-132&rft.issn=1359-4184&rft.eissn=1476-5578&rft_id=info:doi/10.1038/mp.2016.254&rft_dat=%3Cgale_pubme%3EA521121936%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1983675197&rft_id=info:pmid/28115742&rft_galeid=A521121936&rfr_iscdi=true |