Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models
Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of per...
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| description | Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia. |
| doi_str_mv | 10.1371/journal.pone.0216463 |
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Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0216463</identifier><identifier>PMID: 31185023</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animal cognition ; Animal models ; Animals ; Aripiprazole ; Azepines - pharmacology ; Azepines - therapeutic use ; Biology and life sciences ; Blood cells ; Brain ; Brain-derived neurotrophic factor ; Brain-Derived Neurotrophic Factor - genetics ; Cerebral Cortex - drug effects ; Cerebral Cortex - metabolism ; Chromatin ; Clinical outcomes ; Cocaine ; Cortex ; Deoxyribonucleic acid ; DNA ; DNA methylation ; Dopamine ; EDTA ; Enzyme Inhibitors - pharmacology ; Enzyme Inhibitors - therapeutic use ; Enzymes ; Epigenetics ; Feasibility studies ; Female ; Gene expression ; Gene Expression Regulation - drug effects ; Genes ; Genetic aspects ; Glutamate decarboxylase ; Histone Code - drug effects ; Histone methyltransferase ; Histone Methyltransferases - antagonists & inhibitors ; Histones ; Histones - metabolism ; Humans ; Immunoprecipitation ; Inhibitors ; Interleukin 6 ; KLF4 protein ; Leukocytes (mononuclear) ; Leukocytes, Mononuclear - drug effects ; Leukocytes, Mononuclear - metabolism ; Liquid oxygen ; Lurasidone ; Male ; Medicine and Health Sciences ; Mental disorders ; Messenger RNA ; Methyltransferases ; Mice ; Mutation ; Neostriatum ; Neurons ; Paliperidone ; Peripheral blood mononuclear cells ; Pharmacology ; Physical Sciences ; Polymerase chain reaction ; Psychiatry ; Quinazolines - pharmacology ; Quinazolines - therapeutic use ; Research and Analysis Methods ; RNA ; RNA, Messenger - genetics ; Schizophrenia ; Schizophrenia - blood ; Schizophrenia - drug therapy ; Schizophrenia - genetics ; Smoking ; Social research ; Transcription ; Transcription (Genetics) ; Transferases</subject><ispartof>PloS one, 2019-06, Vol.14 (6), p.e0216463</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Chase et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Chase et al 2019 Chase et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-95ea33ed4fad952ce02e31211d84f4a0a6703b2582209f9c8d9bf8bf9f5a632d3</citedby><cites>FETCH-LOGICAL-c692t-95ea33ed4fad952ce02e31211d84f4a0a6703b2582209f9c8d9bf8bf9f5a632d3</cites><orcidid>0000-0002-6783-8604</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/PMC6559633/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6559633/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31185023$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chase, Kayla A</creatorcontrib><creatorcontrib>Feiner, Benjamin</creatorcontrib><creatorcontrib>Ramaker, Marcia J</creatorcontrib><creatorcontrib>Hu, Edward</creatorcontrib><creatorcontrib>Rosen, Cherise</creatorcontrib><creatorcontrib>Sharma, Rajiv P</creatorcontrib><title>Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.</description><subject>Animal cognition</subject><subject>Animal models</subject><subject>Animals</subject><subject>Aripiprazole</subject><subject>Azepines - pharmacology</subject><subject>Azepines - therapeutic use</subject><subject>Biology and life sciences</subject><subject>Blood cells</subject><subject>Brain</subject><subject>Brain-derived neurotrophic factor</subject><subject>Brain-Derived Neurotrophic Factor - genetics</subject><subject>Cerebral Cortex - drug effects</subject><subject>Cerebral Cortex - metabolism</subject><subject>Chromatin</subject><subject>Clinical outcomes</subject><subject>Cocaine</subject><subject>Cortex</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Dopamine</subject><subject>EDTA</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Enzyme Inhibitors - therapeutic use</subject><subject>Enzymes</subject><subject>Epigenetics</subject><subject>Feasibility studies</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation - drug effects</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Glutamate decarboxylase</subject><subject>Histone Code - drug effects</subject><subject>Histone methyltransferase</subject><subject>Histone Methyltransferases - antagonists & inhibitors</subject><subject>Histones</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Inhibitors</subject><subject>Interleukin 6</subject><subject>KLF4 protein</subject><subject>Leukocytes (mononuclear)</subject><subject>Leukocytes, Mononuclear - drug effects</subject><subject>Leukocytes, Mononuclear - metabolism</subject><subject>Liquid oxygen</subject><subject>Lurasidone</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Mental disorders</subject><subject>Messenger RNA</subject><subject>Methyltransferases</subject><subject>Mice</subject><subject>Mutation</subject><subject>Neostriatum</subject><subject>Neurons</subject><subject>Paliperidone</subject><subject>Peripheral blood mononuclear cells</subject><subject>Pharmacology</subject><subject>Physical Sciences</subject><subject>Polymerase chain reaction</subject><subject>Psychiatry</subject><subject>Quinazolines - pharmacology</subject><subject>Quinazolines - therapeutic use</subject><subject>Research and Analysis Methods</subject><subject>RNA</subject><subject>RNA, Messenger - genetics</subject><subject>Schizophrenia</subject><subject>Schizophrenia - blood</subject><subject>Schizophrenia - drug therapy</subject><subject>Schizophrenia - genetics</subject><subject>Smoking</subject><subject>Social research</subject><subject>Transcription</subject><subject>Transcription (Genetics)</subject><subject>Transferases</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><sourceid>DOA</sourceid><recordid>eNqNk19r1TAYxosobk6_gWhAELw4x_xpcpobYY6pBwYD_-FdSNOkzWibLknl7Av5Oc16unkKCtKLNG9_z_OGJ32z7DmCa0Q26O2VG30v2_Xger2GGLGckQfZMeIErxiG5OHB-1H2JIQrCCkpGHucHRGECgoxOc5-ne9kZ3vb1yA2GmhjtIoBODNtGxtisgedjs1NG73sg9FeBg1s39jSRufB--2PFUSY58D1fwSussYqGa3rA5B9BWqdyno3eB1CKiYDULrYAAlUm_or2YLBDWM7SSZF58YwOek2PM0eGdkG_WxeT7JvH86_nn1aXVx-3J6dXqwU4ziuONWSEF3lRlacYqUh1gRhhKoiN7mEkm0gKTEtMIbccFVUvDRFabihkhFckZPs5d53aF0Qc8RBYJyCg0nEErHdE5WTV2LwtpP-RjhpxVRwvhbSR6taLTa0KFGO8AYyniPOSl6Q1JeWWCpayjx5vZu7jWWnK6X7FHG7MF1-6W0javdTMEo5IyQZvJoNvLsedYj_OPJM1TKdyvbGJTPV2aDEKS0KWmzygiZq_RcqPZXurEqXamyqLwRvFoLERL2LtRxDENsvn_-fvfy-ZF8fsI2WbWyCa8fpX1qC-R5U3oXgtblPDkFxOyN3aYjbGRHzjCTZi8PU70V3Q0F-AzUhDlk</recordid><startdate>20190611</startdate><enddate>20190611</enddate><creator>Chase, Kayla A</creator><creator>Feiner, Benjamin</creator><creator>Ramaker, Marcia J</creator><creator>Hu, Edward</creator><creator>Rosen, Cherise</creator><creator>Sharma, Rajiv P</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6783-8604</orcidid></search><sort><creationdate>20190611</creationdate><title>Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models</title><author>Chase, Kayla A ; Feiner, Benjamin ; Ramaker, Marcia J ; Hu, Edward ; Rosen, Cherise ; Sharma, Rajiv P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-95ea33ed4fad952ce02e31211d84f4a0a6703b2582209f9c8d9bf8bf9f5a632d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Animal cognition</topic><topic>Animal models</topic><topic>Animals</topic><topic>Aripiprazole</topic><topic>Azepines - 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Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content 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>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chase, Kayla A</au><au>Feiner, Benjamin</au><au>Ramaker, Marcia J</au><au>Hu, Edward</au><au>Rosen, Cherise</au><au>Sharma, Rajiv P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-06-11</date><risdate>2019</risdate><volume>14</volume><issue>6</issue><spage>e0216463</spage><pages>e0216463-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31185023</pmid><doi>10.1371/journal.pone.0216463</doi><tpages>e0216463</tpages><orcidid>https://orcid.org/0000-0002-6783-8604</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-06, Vol.14 (6), p.e0216463 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2238602206 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animal cognition Animal models Animals Aripiprazole Azepines - pharmacology Azepines - therapeutic use Biology and life sciences Blood cells Brain Brain-derived neurotrophic factor Brain-Derived Neurotrophic Factor - genetics Cerebral Cortex - drug effects Cerebral Cortex - metabolism Chromatin Clinical outcomes Cocaine Cortex Deoxyribonucleic acid DNA DNA methylation Dopamine EDTA Enzyme Inhibitors - pharmacology Enzyme Inhibitors - therapeutic use Enzymes Epigenetics Feasibility studies Female Gene expression Gene Expression Regulation - drug effects Genes Genetic aspects Glutamate decarboxylase Histone Code - drug effects Histone methyltransferase Histone Methyltransferases - antagonists & inhibitors Histones Histones - metabolism Humans Immunoprecipitation Inhibitors Interleukin 6 KLF4 protein Leukocytes (mononuclear) Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - metabolism Liquid oxygen Lurasidone Male Medicine and Health Sciences Mental disorders Messenger RNA Methyltransferases Mice Mutation Neostriatum Neurons Paliperidone Peripheral blood mononuclear cells Pharmacology Physical Sciences Polymerase chain reaction Psychiatry Quinazolines - pharmacology Quinazolines - therapeutic use Research and Analysis Methods RNA RNA, Messenger - genetics Schizophrenia Schizophrenia - blood Schizophrenia - drug therapy Schizophrenia - genetics Smoking Social research Transcription Transcription (Genetics) Transferases |
| title | Examining the effects of the histone methyltransferase inhibitor BIX-01294 on histone modifications and gene expression in both a clinical population and mouse models |
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