Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome
Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not...
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| Veröffentlicht in: | Science advances 2021-05, Vol.7 (21) |
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| container_title | Science advances |
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| creator | Kim, Seung-Kyoon Liu, Xihui Park, Jongmin Um, Dahun Kilaru, Gokhul Chiang, Cheng-Ming Kang, Mingon Huber, Kimberly M Kang, Keunsoo Kim, Tae-Kyung |
| description | Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity. |
| doi_str_mv | 10.1126/sciadv.abf7346 |
| format | Article |
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Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><identifier>DOI: 10.1126/sciadv.abf7346</identifier><identifier>PMID: 34138732</identifier><language>eng</language><publisher>United States: American Association for the Advancement of Science</publisher><subject>Animals ; Fragile X Syndrome - genetics ; Gene Expression Regulation ; Histones - metabolism ; Mice ; Molecular Biology ; Neuroscience ; Nuclear Proteins - genetics ; Nuclear Proteins - metabolism ; SciAdv r-articles ; Transcription Factors - genetics ; Transcription Factors - metabolism</subject><ispartof>Science advances, 2021-05, Vol.7 (21)</ispartof><rights>Copyright © 2021 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 License 4.0 (CC BY).</rights><rights>Copyright © 2021 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 License 4.0 (CC BY). 2021 The Authors</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-73f5c3e83e88636187c74a311f0d577ee65780847414d2282a0c04037ba280663</citedby><cites>FETCH-LOGICAL-c390t-73f5c3e83e88636187c74a311f0d577ee65780847414d2282a0c04037ba280663</cites><orcidid>0000-0001-9776-4047 ; 0000-0002-9565-9523 ; 0000-0002-7479-0661 ; 0000-0002-9716-1032 ; 0000-0003-0208-0051 ; 0000-0001-5161-9864 ; 0000-0003-0611-9320</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/PMC8133748/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8133748/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34138732$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Seung-Kyoon</creatorcontrib><creatorcontrib>Liu, Xihui</creatorcontrib><creatorcontrib>Park, Jongmin</creatorcontrib><creatorcontrib>Um, Dahun</creatorcontrib><creatorcontrib>Kilaru, Gokhul</creatorcontrib><creatorcontrib>Chiang, Cheng-Ming</creatorcontrib><creatorcontrib>Kang, Mingon</creatorcontrib><creatorcontrib>Huber, Kimberly M</creatorcontrib><creatorcontrib>Kang, Keunsoo</creatorcontrib><creatorcontrib>Kim, Tae-Kyung</creatorcontrib><title>Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome</title><title>Science advances</title><addtitle>Sci Adv</addtitle><description>Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. Our study emphasizes the importance of understanding the BET coordination controlled by a balanced action between HATs with different substrate specificity.</description><subject>Animals</subject><subject>Fragile X Syndrome - genetics</subject><subject>Gene Expression Regulation</subject><subject>Histones - metabolism</subject><subject>Mice</subject><subject>Molecular Biology</subject><subject>Neuroscience</subject><subject>Nuclear Proteins - genetics</subject><subject>Nuclear Proteins - metabolism</subject><subject>SciAdv r-articles</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1rHDEMHUpLE5Jccyw-9rJbf43tvRTakLSFQC4p5Ga0Hk3i4o-p7UnZP9Df3Ul3G1IQSEJPTw-9rjtndM0YVx-q8zA8rmE7aiHVq-6YC92veC_N6xf1UXdW6w9KKZNK9WzztjsSkgmjBT_ufl_NyTWfEwTici6DT_DUkjySz5e3ZITow45MJTf0qZI5DViCx0ogNCw4kFYgVVf89HcNas2LqrYMfvn2QCLGXHbExwl8iZga8YmMBe59QHJH6i4NJUc87d6MECqeHfJJ9_3q8vbi6-r65su3i0_XKyc2tK20GHsn0CxhlFDMaKclCMZGOvRaI6peG2qklkwOnBsO1FFJhd4CN1QpcdJ93PNO8zbi4BZBBYKdio9QdjaDt_9Pkn-w9_nRGiaElmYheH8gKPnnjLXZ6KvDECBhnqtdHi6k1P2GL9D1HupKrrXg-HyGUfvkn937Zw_-LQvvXop7hv9zS_wB0DSbmQ</recordid><startdate>20210501</startdate><enddate>20210501</enddate><creator>Kim, Seung-Kyoon</creator><creator>Liu, Xihui</creator><creator>Park, Jongmin</creator><creator>Um, Dahun</creator><creator>Kilaru, Gokhul</creator><creator>Chiang, Cheng-Ming</creator><creator>Kang, Mingon</creator><creator>Huber, Kimberly M</creator><creator>Kang, Keunsoo</creator><creator>Kim, Tae-Kyung</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/0000-0001-9776-4047</orcidid><orcidid>https://orcid.org/0000-0002-9565-9523</orcidid><orcidid>https://orcid.org/0000-0002-7479-0661</orcidid><orcidid>https://orcid.org/0000-0002-9716-1032</orcidid><orcidid>https://orcid.org/0000-0003-0208-0051</orcidid><orcidid>https://orcid.org/0000-0001-5161-9864</orcidid><orcidid>https://orcid.org/0000-0003-0611-9320</orcidid></search><sort><creationdate>20210501</creationdate><title>Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome</title><author>Kim, Seung-Kyoon ; Liu, Xihui ; Park, Jongmin ; Um, Dahun ; Kilaru, Gokhul ; Chiang, Cheng-Ming ; Kang, Mingon ; Huber, Kimberly M ; Kang, Keunsoo ; Kim, Tae-Kyung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-73f5c3e83e88636187c74a311f0d577ee65780847414d2282a0c04037ba280663</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Fragile X Syndrome - genetics</topic><topic>Gene Expression Regulation</topic><topic>Histones - metabolism</topic><topic>Mice</topic><topic>Molecular Biology</topic><topic>Neuroscience</topic><topic>Nuclear Proteins - genetics</topic><topic>Nuclear Proteins - metabolism</topic><topic>SciAdv r-articles</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Seung-Kyoon</creatorcontrib><creatorcontrib>Liu, Xihui</creatorcontrib><creatorcontrib>Park, Jongmin</creatorcontrib><creatorcontrib>Um, Dahun</creatorcontrib><creatorcontrib>Kilaru, Gokhul</creatorcontrib><creatorcontrib>Chiang, Cheng-Ming</creatorcontrib><creatorcontrib>Kang, Mingon</creatorcontrib><creatorcontrib>Huber, Kimberly M</creatorcontrib><creatorcontrib>Kang, Keunsoo</creatorcontrib><creatorcontrib>Kim, Tae-Kyung</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>Kim, Seung-Kyoon</au><au>Liu, Xihui</au><au>Park, Jongmin</au><au>Um, Dahun</au><au>Kilaru, Gokhul</au><au>Chiang, Cheng-Ming</au><au>Kang, Mingon</au><au>Huber, Kimberly M</au><au>Kang, Keunsoo</au><au>Kim, Tae-Kyung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome</atitle><jtitle>Science advances</jtitle><addtitle>Sci Adv</addtitle><date>2021-05-01</date><risdate>2021</risdate><volume>7</volume><issue>21</issue><issn>2375-2548</issn><eissn>2375-2548</eissn><abstract>Bromodomain and extraterminal proteins (BET) are epigenetic readers that play critical roles in gene regulation. Pharmacologic inhibition of the bromodomain present in all BET family members is a promising therapeutic strategy for various diseases, but its impact on individual family members has not been well understood. Using a transcriptional induction paradigm in neurons, we have systematically demonstrated that three major BET family proteins (BRD2/3/4) participated in transcription with different recruitment kinetics, interdependency, and sensitivity to a bromodomain inhibitor, JQ1. In a mouse model of fragile X syndrome (FXS), BRD2/3 and BRD4 showed oppositely altered expression and chromatin binding, correlating with transcriptional dysregulation. Acute inhibition of CBP/p300 histone acetyltransferase (HAT) activity restored the altered binding patterns of BRD2 and BRD4 and rescued memory impairment in FXS. 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| subjects | Animals Fragile X Syndrome - genetics Gene Expression Regulation Histones - metabolism Mice Molecular Biology Neuroscience Nuclear Proteins - genetics Nuclear Proteins - metabolism SciAdv r-articles Transcription Factors - genetics Transcription Factors - metabolism |
| title | Functional coordination of BET family proteins underlies altered transcription associated with memory impairment in fragile X syndrome |
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