Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer
Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluo...
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| creator | Yan, Kezhi Rousseau, Justine Machol, Keren Cross, Laura A Agre, Katherine E Gibson, Cynthia Forster Goverde, Anne Engleman, Kendra L Verdin, Hannah De Baere, Elfride Potocki, Lorraine Zhou, Dihong Cadieux-Dion, Maxime Bellus, Gary A Wagner, Monisa D Hale, Rebecca J Esber, Natacha Riley, Alan F Solomon, Benjamin D Cho, Megan T McWalter, Kirsty Eyal, Roy Hainlen, Meagan K Mendelsohn, Bryce A Porter, Hillary M Lanpher, Brendan C Lewis, Andrea M Savatt, Juliann Thiffault, Isabelle Callewaert, Bert Campeau, Philippe M Yang, Xiang-Jiao |
| description | Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation. |
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We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.</description><identifier>ISSN: 2375-2548</identifier><identifier>EISSN: 2375-2548</identifier><language>eng</language><subject>ACETYLATION ; EXPRESSION ; GENE ; GENOME ; H3K14 ; HBO1 ACETYLTRANSFERASE ; KAT6B ; Medicine and Health Sciences ; MUTATIONS ; RECOGNITION ; REGULATOR BRPF1</subject><creationdate>2020</creationdate><rights>Creative Commons Attribution-NonCommercial 4.0 International Public License (CC BY-NC 4.0) info:eu-repo/semantics/openAccess</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,315,776,780,4010,27837</link.rule.ids></links><search><creatorcontrib>Yan, Kezhi</creatorcontrib><creatorcontrib>Rousseau, Justine</creatorcontrib><creatorcontrib>Machol, Keren</creatorcontrib><creatorcontrib>Cross, Laura A</creatorcontrib><creatorcontrib>Agre, Katherine E</creatorcontrib><creatorcontrib>Gibson, Cynthia Forster</creatorcontrib><creatorcontrib>Goverde, Anne</creatorcontrib><creatorcontrib>Engleman, Kendra L</creatorcontrib><creatorcontrib>Verdin, Hannah</creatorcontrib><creatorcontrib>De Baere, Elfride</creatorcontrib><creatorcontrib>Potocki, Lorraine</creatorcontrib><creatorcontrib>Zhou, Dihong</creatorcontrib><creatorcontrib>Cadieux-Dion, Maxime</creatorcontrib><creatorcontrib>Bellus, Gary A</creatorcontrib><creatorcontrib>Wagner, Monisa D</creatorcontrib><creatorcontrib>Hale, Rebecca J</creatorcontrib><creatorcontrib>Esber, Natacha</creatorcontrib><creatorcontrib>Riley, Alan F</creatorcontrib><creatorcontrib>Solomon, Benjamin D</creatorcontrib><creatorcontrib>Cho, Megan T</creatorcontrib><creatorcontrib>McWalter, Kirsty</creatorcontrib><creatorcontrib>Eyal, Roy</creatorcontrib><creatorcontrib>Hainlen, Meagan K</creatorcontrib><creatorcontrib>Mendelsohn, Bryce A</creatorcontrib><creatorcontrib>Porter, Hillary M</creatorcontrib><creatorcontrib>Lanpher, Brendan C</creatorcontrib><creatorcontrib>Lewis, Andrea M</creatorcontrib><creatorcontrib>Savatt, Juliann</creatorcontrib><creatorcontrib>Thiffault, Isabelle</creatorcontrib><creatorcontrib>Callewaert, Bert</creatorcontrib><creatorcontrib>Campeau, Philippe M</creatorcontrib><creatorcontrib>Yang, Xiang-Jiao</creatorcontrib><title>Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer</title><description>Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). 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These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation.</description><subject>ACETYLATION</subject><subject>EXPRESSION</subject><subject>GENE</subject><subject>GENOME</subject><subject>H3K14</subject><subject>HBO1 ACETYLTRANSFERASE</subject><subject>KAT6B</subject><subject>Medicine and Health Sciences</subject><subject>MUTATIONS</subject><subject>RECOGNITION</subject><subject>REGULATOR BRPF1</subject><issn>2375-2548</issn><issn>2375-2548</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>ADGLB</sourceid><recordid>eNqdjMsKwjAQRYMoKOo_zA8U-rCxLn0iuBHpPqTptB2JSUmq6N9bwYVrV-fA5dwBm8TJMg3idJENf3zM5t5fwzCMFpyn0WrCqh1WpAhNBw35zhqEYwKtsy1Z89Ky6wHFCzaX8yEKTuucg7K3VuMTPZABg3dnS3ygtu2tf5EaSvLWleg8SFOCkkahm7FRJbXH-ZdTFh_2-fYY1E0fCU2FQyU7YSUJ6VRDDxT3-jMVKDLOlzxOkr-iN_XrVYY</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>Yan, Kezhi</creator><creator>Rousseau, Justine</creator><creator>Machol, Keren</creator><creator>Cross, Laura A</creator><creator>Agre, Katherine E</creator><creator>Gibson, Cynthia Forster</creator><creator>Goverde, Anne</creator><creator>Engleman, Kendra L</creator><creator>Verdin, Hannah</creator><creator>De Baere, Elfride</creator><creator>Potocki, Lorraine</creator><creator>Zhou, Dihong</creator><creator>Cadieux-Dion, Maxime</creator><creator>Bellus, Gary A</creator><creator>Wagner, Monisa D</creator><creator>Hale, Rebecca J</creator><creator>Esber, Natacha</creator><creator>Riley, Alan F</creator><creator>Solomon, Benjamin D</creator><creator>Cho, Megan T</creator><creator>McWalter, Kirsty</creator><creator>Eyal, Roy</creator><creator>Hainlen, Meagan K</creator><creator>Mendelsohn, Bryce A</creator><creator>Porter, Hillary M</creator><creator>Lanpher, Brendan C</creator><creator>Lewis, Andrea M</creator><creator>Savatt, Juliann</creator><creator>Thiffault, Isabelle</creator><creator>Callewaert, Bert</creator><creator>Campeau, Philippe M</creator><creator>Yang, Xiang-Jiao</creator><scope>ADGLB</scope></search><sort><creationdate>2020</creationdate><title>Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer</title><author>Yan, Kezhi ; 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| source | Ghent University Academic Bibliography; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
| subjects | ACETYLATION EXPRESSION GENE GENOME H3K14 HBO1 ACETYLTRANSFERASE KAT6B Medicine and Health Sciences MUTATIONS RECOGNITION REGULATOR BRPF1 |
| title | Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer |
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