Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing
Abstract CRISPR-based base editors (BEs) are widely used to induce nucleotide substitutions in living cells and organisms without causing the damaging DNA double-strand breaks and DNA donor templates. Cytosine BEs that induce C:G to T:A conversion and adenine BEs that induce A:T to G:C conversion ha...
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| Veröffentlicht in: | Nucleic acids research 2021-02, Vol.49 (4), p.2390-2399 |
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| creator | Shin, Ha Rim See, Ji-Eun Kweon, Jiyeon Kim, Heon Seok Sung, Gi-Jun Park, Sojung Jang, An-Hee Jang, Gayoung Choi, Kyung‐Chul Kim, Inki Kim, Jin-Soo Kim, Yongsub |
| description | Abstract
CRISPR-based base editors (BEs) are widely used to induce nucleotide substitutions in living cells and organisms without causing the damaging DNA double-strand breaks and DNA donor templates. Cytosine BEs that induce C:G to T:A conversion and adenine BEs that induce A:T to G:C conversion have been developed. Various attempts have been made to increase the efficiency of both BEs; however, their activities need to be improved for further applications. Here, we describe a fluorescent reporter-based drug screening platform to identify novel chemicals with the goal of improving adenine base editing efficiency. The reporter system revealed that histone deacetylase inhibitors, particularly romidepsin, enhanced base editing efficiencies by up to 4.9-fold by increasing the expression levels of proteins and target accessibility. The results support the use of romidepsin as a viable option to improve base editing efficiency in biomedical research and therapeutic genome engineering. |
| doi_str_mv | 10.1093/nar/gkab052 |
| format | Article |
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CRISPR-based base editors (BEs) are widely used to induce nucleotide substitutions in living cells and organisms without causing the damaging DNA double-strand breaks and DNA donor templates. Cytosine BEs that induce C:G to T:A conversion and adenine BEs that induce A:T to G:C conversion have been developed. Various attempts have been made to increase the efficiency of both BEs; however, their activities need to be improved for further applications. Here, we describe a fluorescent reporter-based drug screening platform to identify novel chemicals with the goal of improving adenine base editing efficiency. The reporter system revealed that histone deacetylase inhibitors, particularly romidepsin, enhanced base editing efficiencies by up to 4.9-fold by increasing the expression levels of proteins and target accessibility. The results support the use of romidepsin as a viable option to improve base editing efficiency in biomedical research and therapeutic genome engineering.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab052</identifier><identifier>PMID: 33544854</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Adenine ; CRISPR-Cas Systems ; Depsipeptides - pharmacology ; Doxycycline - pharmacology ; Gene Editing ; Green Fluorescent Proteins - analysis ; Green Fluorescent Proteins - genetics ; HEK293 Cells ; HeLa Cells ; Histone Deacetylase Inhibitors - pharmacology ; Humans ; Luminescent Agents - analysis ; Protein Biosynthesis ; RNA - biosynthesis ; Synthetic Biology and Bioengineering</subject><ispartof>Nucleic acids research, 2021-02, Vol.49 (4), p.2390-2399</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-6004b8d4d418381c7ffb9c5e0184d4fc40303d48657ef9898590364541b7f5c63</citedby><cites>FETCH-LOGICAL-c412t-6004b8d4d418381c7ffb9c5e0184d4fc40303d48657ef9898590364541b7f5c63</cites><orcidid>0000-0002-9334-4333</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/PMC7913676/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913676/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1604,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33544854$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shin, Ha Rim</creatorcontrib><creatorcontrib>See, Ji-Eun</creatorcontrib><creatorcontrib>Kweon, Jiyeon</creatorcontrib><creatorcontrib>Kim, Heon Seok</creatorcontrib><creatorcontrib>Sung, Gi-Jun</creatorcontrib><creatorcontrib>Park, Sojung</creatorcontrib><creatorcontrib>Jang, An-Hee</creatorcontrib><creatorcontrib>Jang, Gayoung</creatorcontrib><creatorcontrib>Choi, Kyung‐Chul</creatorcontrib><creatorcontrib>Kim, Inki</creatorcontrib><creatorcontrib>Kim, Jin-Soo</creatorcontrib><creatorcontrib>Kim, Yongsub</creatorcontrib><title>Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
CRISPR-based base editors (BEs) are widely used to induce nucleotide substitutions in living cells and organisms without causing the damaging DNA double-strand breaks and DNA donor templates. Cytosine BEs that induce C:G to T:A conversion and adenine BEs that induce A:T to G:C conversion have been developed. Various attempts have been made to increase the efficiency of both BEs; however, their activities need to be improved for further applications. Here, we describe a fluorescent reporter-based drug screening platform to identify novel chemicals with the goal of improving adenine base editing efficiency. The reporter system revealed that histone deacetylase inhibitors, particularly romidepsin, enhanced base editing efficiencies by up to 4.9-fold by increasing the expression levels of proteins and target accessibility. The results support the use of romidepsin as a viable option to improve base editing efficiency in biomedical research and therapeutic genome engineering.</description><subject>Adenine</subject><subject>CRISPR-Cas Systems</subject><subject>Depsipeptides - pharmacology</subject><subject>Doxycycline - pharmacology</subject><subject>Gene Editing</subject><subject>Green Fluorescent Proteins - analysis</subject><subject>Green Fluorescent Proteins - genetics</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Histone Deacetylase Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Luminescent Agents - analysis</subject><subject>Protein Biosynthesis</subject><subject>RNA - biosynthesis</subject><subject>Synthetic Biology and Bioengineering</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kUtLxDAUhYMoOj5W7qUrEaRO0iRtuhFk8AWCMurGTUjT25lo2oxJK_jvzTCj6MZVyMnHyb3nIHRI8BnBJR13yo9nb6rCPNtAI0LzLGVlnm2iEaaYpwQzsYN2Q3jFmDDC2TbaoZQzJjgboZfHVlmbts6CHiwkppubyvTOh8Q1ydyE3nWQ1KA09J9WhUi0C-8-IJlMbx8fpmkVtTpRNXQmgstbArXpTTfbR1uNsgEO1uceer66fJrcpHf317eTi7tUM5L1aY4xq0TNakYEFUQXTVOVmgMmImqNZnELWjOR8wKaUpSCl5jmjDNSFQ3XOd1D5yvfxVC1UGvoeq-sXHjTKv8pnTLy70tn5nLmPmRRxrCKpcHJ2sC79wFCL1sTNFirOnBDkBkTBeFlDC-ipytUexeCh-bnG4Llsg0Z25DrNiJ99HuyH_Y7_ggcrwA3LP51-gK57ZRy</recordid><startdate>20210226</startdate><enddate>20210226</enddate><creator>Shin, Ha Rim</creator><creator>See, Ji-Eun</creator><creator>Kweon, Jiyeon</creator><creator>Kim, Heon Seok</creator><creator>Sung, Gi-Jun</creator><creator>Park, Sojung</creator><creator>Jang, An-Hee</creator><creator>Jang, Gayoung</creator><creator>Choi, Kyung‐Chul</creator><creator>Kim, Inki</creator><creator>Kim, Jin-Soo</creator><creator>Kim, Yongsub</creator><general>Oxford University Press</general><scope>TOX</scope><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/0000-0002-9334-4333</orcidid></search><sort><creationdate>20210226</creationdate><title>Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing</title><author>Shin, Ha Rim ; See, Ji-Eun ; Kweon, Jiyeon ; Kim, Heon Seok ; Sung, Gi-Jun ; Park, Sojung ; Jang, An-Hee ; Jang, Gayoung ; Choi, Kyung‐Chul ; Kim, Inki ; Kim, Jin-Soo ; Kim, Yongsub</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-6004b8d4d418381c7ffb9c5e0184d4fc40303d48657ef9898590364541b7f5c63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adenine</topic><topic>CRISPR-Cas Systems</topic><topic>Depsipeptides - pharmacology</topic><topic>Doxycycline - pharmacology</topic><topic>Gene Editing</topic><topic>Green Fluorescent Proteins - analysis</topic><topic>Green Fluorescent Proteins - genetics</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Histone Deacetylase Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Luminescent Agents - analysis</topic><topic>Protein Biosynthesis</topic><topic>RNA - biosynthesis</topic><topic>Synthetic Biology and Bioengineering</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shin, Ha Rim</creatorcontrib><creatorcontrib>See, Ji-Eun</creatorcontrib><creatorcontrib>Kweon, Jiyeon</creatorcontrib><creatorcontrib>Kim, Heon Seok</creatorcontrib><creatorcontrib>Sung, Gi-Jun</creatorcontrib><creatorcontrib>Park, Sojung</creatorcontrib><creatorcontrib>Jang, An-Hee</creatorcontrib><creatorcontrib>Jang, Gayoung</creatorcontrib><creatorcontrib>Choi, Kyung‐Chul</creatorcontrib><creatorcontrib>Kim, Inki</creatorcontrib><creatorcontrib>Kim, Jin-Soo</creatorcontrib><creatorcontrib>Kim, Yongsub</creatorcontrib><collection>Access via Oxford University Press (Open Access Collection)</collection><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>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shin, Ha Rim</au><au>See, Ji-Eun</au><au>Kweon, Jiyeon</au><au>Kim, Heon Seok</au><au>Sung, Gi-Jun</au><au>Park, Sojung</au><au>Jang, An-Hee</au><au>Jang, Gayoung</au><au>Choi, Kyung‐Chul</au><au>Kim, Inki</au><au>Kim, Jin-Soo</au><au>Kim, Yongsub</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-02-26</date><risdate>2021</risdate><volume>49</volume><issue>4</issue><spage>2390</spage><epage>2399</epage><pages>2390-2399</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
CRISPR-based base editors (BEs) are widely used to induce nucleotide substitutions in living cells and organisms without causing the damaging DNA double-strand breaks and DNA donor templates. Cytosine BEs that induce C:G to T:A conversion and adenine BEs that induce A:T to G:C conversion have been developed. Various attempts have been made to increase the efficiency of both BEs; however, their activities need to be improved for further applications. Here, we describe a fluorescent reporter-based drug screening platform to identify novel chemicals with the goal of improving adenine base editing efficiency. The reporter system revealed that histone deacetylase inhibitors, particularly romidepsin, enhanced base editing efficiencies by up to 4.9-fold by increasing the expression levels of proteins and target accessibility. The results support the use of romidepsin as a viable option to improve base editing efficiency in biomedical research and therapeutic genome engineering.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33544854</pmid><doi>10.1093/nar/gkab052</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-9334-4333</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adenine CRISPR-Cas Systems Depsipeptides - pharmacology Doxycycline - pharmacology Gene Editing Green Fluorescent Proteins - analysis Green Fluorescent Proteins - genetics HEK293 Cells HeLa Cells Histone Deacetylase Inhibitors - pharmacology Humans Luminescent Agents - analysis Protein Biosynthesis RNA - biosynthesis Synthetic Biology and Bioengineering |
| title | Small-molecule inhibitors of histone deacetylase improve CRISPR-based adenine base editing |
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