HDAC1 and HDAC2 are bidirectional enzymes that catalyze histone sorbylation to induce epigenetic alterations

HDAC1 and HDAC2 are bidirectional enzymes that catalyze histone sorbylation to induce epigenetic alterations | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article HDAC1 and HDAC2 are bidirectional enzymes that catalyze histone sorbylation to induce epigenetic alterations Akihiro Ito, Kota Noritsugu, Yuki Shimizu, Takehiro Suzuki, Komei Aoki, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5847857/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Reversible histone acylation is crucial for epigenetic gene expression regulation. Histone acylation is typically mediated by lysine acyltransferases (KATs), which use acyl-CoAs as acyl donors. Here, we revealed the novel role of the histone deacetylases HDAC1 and HDAC2 in histone acylation catalysis. Notably, we show that HDAC1 and HDAC2 directly catalyze sorbylation using sorbic acid, a common food preservative, in addition to facilitating desorbylation. This newly discovered HDAC1/2-driven histone sorbylation function is a distinctive active epigenetic mark that leads to widespread changes in the expression of genes, particularly those involved in cholesterol biosynthesis. Our findings reveal that HDAC1/2 are unique enzymes capable of catalyzing not only the removal but also formation of histone modifications in response to exogenous carboxylic acids such as sorbic acid and benzoic acid. Our results highlight the impact of carboxylic acids found in the environment, such as food additives, on gene expression changes that occur via histone lysine modification regulated by HDAC1 and HDAC2. Biological sciences/Genetics/Epigenomics Biological sciences/Chemical biology/Post-translational modifications/Acetylation Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Full Text Additional Declarations There is NO Competing Interest. IACUC: All animal experiments were conducted in accordance with the animal experimental protocol and guidelines of the Tokyo University of Pharmacy and Life Sciences Animal Experimentation Regulations after review by the Institutional Animal Care and Use Committee (permission number L21-24) and approval by the President of the Tokyo University of Pharmacy and Life Sciences. Supplementary Files SupplementaryNoritsuguetalfinal6.pdf Supplementary Information Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5847857","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":408417193,"identity":"d4bc75b0-2add-4006-b747-90f367aeac84","order_by":0,"name":"Akihiro 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Science","correspondingAuthor":false,"prefix":"","firstName":"Minoru","middleName":"","lastName":"Yoshida","suffix":""},{"id":408417207,"identity":"733c10de-eb05-4187-8936-43aaed342592","order_by":14,"name":"Naoshi Dohmae","email":"","orcid":"https://orcid.org/0000-0002-5242-9410","institution":"RIKEN","correspondingAuthor":false,"prefix":"","firstName":"Naoshi","middleName":"","lastName":"Dohmae","suffix":""},{"id":408417208,"identity":"34f672c3-785c-4312-a5f1-d62d4f82f082","order_by":15,"name":"Yoshito Kumagai","email":"","orcid":"","institution":"Kyushu University","correspondingAuthor":false,"prefix":"","firstName":"Yoshito","middleName":"","lastName":"Kumagai","suffix":""}],"badges":[],"createdAt":"2025-01-17 09:25:20","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5847857/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5847857/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":75141462,"identity":"0b3ee666-af48-4478-ae57-d6585c70acae","added_by":"auto","created_at":"2025-01-31 05:04:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":267311,"visible":true,"origin":"","legend":"\u003cp\u003eSorbic acid can be used for histone lysine sorbylation modifications. a Sorbylated lysine residues in core histones identified by LC‒MS/MS analysis and chemical structure of sorbylated lysine. Each mark indicates the experiment in which the sorbylation site was identified (●, sorbate-treated HepG2 cells; ▲, sorbate-treated HeLa cells; and *, d4-labeled sorbate-treated HepG2 cells). b-c Representative MS/MS spectra of d4-labeled H2BK5sor (b) and H2BK11sor (c). d Specificity of the antibodies generated in this study. Western blotting of the chemically modified recombinant histone H2B was performed using the indicated antibodies (Ac, acetylation; Bu, butyrylation; Cr, crotonylation; and Sor, sorbylation). e Dose dependency of histone sorbylation. HepG2 cells were treated with potassium sorbate at the specified concentrations for 24 h. The histone sorbylation levels were subsequently detected by western blotting using the indicated antibodies. f Time dependency of histone sorbylation. HepG2 cells were treated with 10 mM potassium sorbate for the indicated durations. The histone sorbylation levels were subsequently detected by western blotting using the indicated antibodies.\u0026nbsp;\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/1e8fedbb4ecacdbd61a6d0a5.png"},{"id":75142482,"identity":"f9835172-5ac5-45c1-9559-4a33a2c4171d","added_by":"auto","created_at":"2025-01-31 05:28:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":246214,"visible":true,"origin":"","legend":"\u003cp\u003eHDAC1 and HDAC2 catalyze histone lysine desorbylation. a Reversibility of histone sorbylation in cells. HepG2 cells were treated with 10 mM potassium sorbate for 24 h. Cells were collected at different time points after media exchange, as shown in the figure above. The sorbylation levels were detected by western blotting using the indicated antibodies. b Effects of KDAC inhibitors on desorbylation in cells. Sorbate treatment and medium changes were performed as described in Fig. 2a, and the indicated KDAC inhibitors were administered during medium exchange. The residual sorbylation levels were detected by western blotting using the indicated antibodies (NAM, 5 mM nicotinamide; TSA, 1 µM trichostatin A; and MGCD, 10 µM MGCD0103, and 10 µM MS275). c Desorbylation catalyzed by class I and IV HDACs. FLAG-tagged HDACs purified from HEK293T cells and sorbylated histones extracted from HEK293T cells were incubated in vitro. HA indicates an inactive deacetylase mutant (HDAC1 H141A and HDAC2 H142A). Total histones were visualized by Congo red staining.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/ce34da0c5e39d51a8aa56719.png"},{"id":75141472,"identity":"f3fb0df4-2eb9-4631-bf46-d3b713a34f26","added_by":"auto","created_at":"2025-01-31 05:04:41","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":316682,"visible":true,"origin":"","legend":"\u003cp\u003eHDAC1 and HDAC2 catalyze histone sorbylation in a deacetylase activity dependent manner. a Effect of HDAC inhibitor pretreatment on histone sorbylation. HepG2 cells were treated with the indicated HDAC inhibitors for 1 h, followed by treatment with potassium sorbate for 6 h, resulting in a total of 7 h of treatment with the HDAC inhibitors. The sorbylation levels were detected by western blotting using the indicated antibodies (TSA, 1 µM trichostatin A; MGCD, 10 µM MGCD0103; and PCI, 25 µM PCI-34051, and 10 µM FT-895). b Histone sorbylation by HDAC1/2 using sorbate. FLAG-tagged HDACs purified from HEK293T cells and histones extracted from HEK293T cells were incubated with 10 mM potassium sorbate in vitro. HA indicates an inactive deacetylase mutant (HDAC1 H141A and HDAC2 H142A). Total histones were visualized by Congo red staining. c Histone sorbylation occurred in a sorbate-dependent manner. FLAG-tagged HDAC1 purified from HEK293T cells and histones extracted from HEK293T cells were incubated in vitro with the indicated concentrations of potassium sorbate. d Effect of HDAC1/2 depletion on histone sorbylation. HeLaS3 cells were transfected with 10 nM siHDAC1 and/or 10 nM siHDAC2, with control siRNA added to total 20 nM siRNA. After 72 h, the cells were treated with 5 mM potassium sorbate for 24 h. The sorbylation levels were detected by western blotting. e Schematic of reversible histone sorbylation regulated by HDAC1/2\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/c80a9d04bc4488de44be3613.png"},{"id":75142485,"identity":"be9c8bea-3e55-48a6-8cf3-cca78e220f58","added_by":"auto","created_at":"2025-01-31 05:28:41","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":67996,"visible":true,"origin":"","legend":"\u003cp\u003eSorbic acid upregulates cholesterol synthesis-related genes via histone sorbylation. a, b Enrichment analysis of the upregulated genes in sorbate-treated cells. HepG2 cells were treated with 5 mM potassium sorbate for 24 h. Total RNA was extracted and subjected to RNA-seq analysis. Metascape enrichment analysis (a) was performed on the upregulated genes (fold change \u0026gt; 2, FDR \u0026lt; 0.05). GSEA was performed using logCPM output of edgeR as input Gene Cluster Text file. c mRNA expression levels in sorbate-treated HepG2 cells. HepG2 cells were treated with the indicated concentrations of potassium sorbate for 24 h. Total RNA was extracted, and the mRNA levels were evaluated via RT‒qPCR. d Effect of TSA pretreatment on sorbate-induced mRNA expression. HepG2 cells were treated with 1 µM TSA for 1 h followed by 10 mM potassium sorbate for 24 h. Total RNA was extracted, and mRNA levels were evaluated via RT‒qPCR. e Effect of sorbate treatment on chromatin accessibility. HepG2 cells were treated with 0.5 µM TSA or 10 mM potassium sorbate for 24 h. Chromatin accessibility was assessed by ATAC-see, and the fluorescence intensity was quantified with CellProfiler. EDTA indicates that EDTA was added to the transposase reaction as a negative control for fluorescent probe integration. c, d Data represent the means ± SEMs from three independent experiments. Statistical significance was evaluated by one-way ANOVA followed by Tukey’s multiple comparisons test. e Data were visualized as violin plots and box plots. The following numbers are the numbers of cells used in three independent experiments: EDTA = 875, ctrl = 962, Sorbate = 580, and TSA = 842. Statistical significance was evaluated by the Kruskal‒Wallis test followed by Dunn's multiple comparisons test.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/c8d14e19f29c17ee465f59ac.png"},{"id":75141469,"identity":"0cd2acdb-bbc4-4260-a9bd-9531d79ebbf1","added_by":"auto","created_at":"2025-01-31 05:04:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":50365,"visible":true,"origin":"","legend":"\u003cp\u003eGenome-wide analysis of histone sorbylation. a, b CUT\u0026amp;Tag revealed the peaks of H2BK11sor in the genomic region. HepG2 cells were treated with 10 mM potassium sorbate for 24 h. A CUT\u0026amp;Tag assay was performed using the indicated antibodies. Sequence reads were visualized as a metagene plot (a), and the peaks in the regions of specific genes were visualized using IGV (b). The HDAC1 and HDAC2 peak data obtained from liver tissues were acquired from ChIP Atlas, and the human promoter and enhancer data were obtained from the FANTOM5 project. c Overlapping H2BK11sor and HDAC1/2 peaks. The SEACR-defined H2BK11sor peaks and HDAC1 and HDAC2 peaks from public data in ChIP-Atlas were annotated, and overlapping peaks were evaluated by ChIPpeakAnno. The H2BK11sor peaks that were common in both experiments were used as H2BK11sor peaks. d Annotation of H2BK11sor peaks located between 3 kb upstream of the transcription start sites and the transcription end sites of genes upregulated by potassium sorbate treatment (up) and total genes (total). The peak distribution was annotated by ChIPseeker.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/47185cc0fe11c10ad9820cf0.png"},{"id":75142759,"identity":"0b48f9f0-504b-4418-a4b7-441f7644a44a","added_by":"auto","created_at":"2025-01-31 05:36:44","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1222040,"visible":true,"origin":"","legend":"Article File","description":"","filename":"TextNoritsuguetalfinal4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1_covered_4fa2152e-cca2-44bd-92f0-8d743d66b465.pdf"},{"id":75141466,"identity":"1fe2c23b-4b83-4fe6-9d51-04ce42f9bee7","added_by":"auto","created_at":"2025-01-31 05:04:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12049359,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryNoritsuguetalfinal6.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5847857/v1/da52f60241c80b6d147dad21.pdf"}],"financialInterests":"\u003cp\u003eThere is \u003cstrong\u003eNO\u003c/strong\u003e Competing Interest.\u003c/p\u003e\n\u003cp\u003eIACUC: All animal experiments were conducted in accordance with the animal experimental protocol and guidelines of the Tokyo University of Pharmacy and Life Sciences Animal Experimentation Regulations after review by the Institutional Animal Care and Use Committee (permission number L21-24) and approval by the President of the Tokyo University of Pharmacy and Life Sciences.\u003c/p\u003e","formattedTitle":"HDAC1 and HDAC2 are bidirectional enzymes that catalyze histone sorbylation to induce epigenetic alterations","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5847857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5847857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Reversible histone acylation is crucial for epigenetic gene expression regulation. Histone acylation is typically mediated by lysine acyltransferases (KATs), which use acyl-CoAs as acyl donors. Here, we revealed the novel role of the histone deacetylases HDAC1 and HDAC2 in histone acylation catalysis. Notably, we show that HDAC1 and HDAC2 directly catalyze sorbylation using sorbic acid, a common food preservative, in addition to facilitating desorbylation. This newly discovered HDAC1/2-driven histone sorbylation function is a distinctive active epigenetic mark that leads to widespread changes in the expression of genes, particularly those involved in cholesterol biosynthesis. Our findings reveal that HDAC1/2 are unique enzymes capable of catalyzing not only the removal but also formation of histone modifications in response to exogenous carboxylic acids such as sorbic acid and benzoic acid. Our results highlight the impact of carboxylic acids found in the environment, such as food additives, on gene expression changes that occur via histone lysine modification regulated by HDAC1 and HDAC2.","manuscriptTitle":"HDAC1 and HDAC2 are bidirectional enzymes that catalyze histone sorbylation to induce epigenetic alterations","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-31 05:04:35","doi":"10.21203/rs.3.rs-5847857/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3d02ec8b-d981-44d4-a297-b2eb052b4f51","owner":[],"postedDate":"January 31st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":43546951,"name":"Biological sciences/Genetics/Epigenomics"},{"id":43546952,"name":"Biological sciences/Chemical biology/Post-translational modifications/Acetylation"}],"tags":[],"updatedAt":"2025-03-31T22:40:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-01-31 05:04:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5847857","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5847857","identity":"rs-5847857","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}