{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:39:06Z","timestamp":1785425946560,"version":"3.56.0"},"reference-count":55,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R37AI083139"],"award-info":[{"award-number":["R37AI083139"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UM1AI164559"],"award-info":[{"award-number":["UM1AI164559"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010296","name":"James B. Pendleton Charitable Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010296","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04tw4j633","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Hellmann Foundation"},{"DOI":"10.13039\/100008072","name":"Gladstone Institutes","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008072","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/038321296","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The lysine methyltransferase SMYD5 is an important regulator of development and has been implicated in multiple malignancies, such as heart disease, lung and gastric cancers, breast and hepatocellular carcinomas, and inflammatory bowel disease. Further, SMYD5 has been linked to the mild hypothermia response, RNA translation, and HIV-1 transcription. SMYD5 is ubiquitously expressed in lymphocytes and the fetal brain, retina, heart, gut, liver, and reproductive organs. Mechanistically, SMYD5 methylates histone residues H3K36, H3K37, and H4K20, as well as non-histone targets such as the ribosomal protein RPL40 and the HIV-1 Tat protein. Here, we review the literature on SMYD5, focusing on its epigenetic functions and its roles in development, cancer, and other biological processes.<\/jats:p>","DOI":"10.3390\/ijms27135884","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T08:26:15Z","timestamp":1782807975000},"page":"5884","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Functions of SMYD5 and Its Role in Development, Cancer and Other Cellular Processes"],"prefix":"10.3390","volume":"27","author":[{"given":"Daniela","family":"Boehm","sequence":"first","affiliation":[{"name":"Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanika","family":"Khanna","sequence":"additional","affiliation":[{"name":"Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0331-3208","authenticated-orcid":false,"given":"Zichong","family":"Li","sequence":"additional","affiliation":[{"name":"Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melanie","family":"Ott","sequence":"additional","affiliation":[{"name":"Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, CA 94158, USA"},{"name":"Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA"},{"name":"Chan Zuckerberg Biohub, San Francisco, CA 94158, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1186\/gb-2005-6-8-227","article-title":"The SET-domain protein superfamily: Protein lysine methyltransferases","volume":"6","author":"Dillon","year":"2005","journal-title":"Genome Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1007\/s000180050127","article-title":"SET domain proteins modulate chromatin domains in eu- and heterochromatin","volume":"54","author":"Jenuwein","year":"1998","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4906","DOI":"10.1074\/jbc.M110078200","article-title":"The conserved Mynd domain of BS69 binds cellular and oncoviral proteins through a common PXLXP motif","volume":"277","author":"Ansieau","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.3390\/ijms16011406","article-title":"Structure and function of SET and MYND domain-containing proteins","volume":"16","author":"Spellmon","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.tig.2017.12.011","article-title":"Caught with One\u2019s Zinc Fingers in the Genome Integrity Cookie Jar","volume":"34","author":"Vilas","year":"2018","journal-title":"Trends Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.bbrc.2022.02.043","article-title":"SMYD5 is a histone H3-specific methyltransferase mediating mono-methylation of histone H3 lysine 36 and 37","volume":"599","author":"Aljazi","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3190","DOI":"10.1038\/s41467-022-30940-1","article-title":"SMYD5 catalyzes histone H3 lysine 36 trimethylation at promoters","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.molcel.2012.07.020","article-title":"Control of proinflammatory gene programs by regulated trimethylation and demethylation of histone H4K20","volume":"48","author":"Stender","year":"2012","journal-title":"Mol. Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"112234","DOI":"10.1016\/j.celrep.2023.112234","article-title":"The lysine methyltransferase SMYD5 amplifies HIV-1 transcription and is post-transcriptionally upregulated by Tat and USP11","volume":"42","author":"Boehm","year":"2023","journal-title":"Cell Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1038\/s41586-024-07718-0","article-title":"SMYD5 methylation of rpL40 links ribosomal output to gastric cancer","volume":"632","author":"Park","year":"2024","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1038\/s41422-024-01013-3","article-title":"SMYD5 is a ribosomal methyltransferase that catalyzes RPL40 lysine methylation to enhance translation output and promote hepatocellular carcinoma","volume":"34","author":"Miao","year":"2024","journal-title":"Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115518","DOI":"10.1016\/j.celrep.2025.115518","article-title":"SMYD5 is a ribosomal methyltransferase that trimethylates RPL40 lysine 22 through recognition of a KXY motif","volume":"44","author":"Hamey","year":"2025","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4337","DOI":"10.1128\/MCB.16.8.4337","article-title":"Isolation of a novel retinoic acid-responsive gene by selection of genomic fragments derived from CpG-island-enriched DNA","volume":"16","author":"Shago","year":"1996","journal-title":"Mol. Cell. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Calpena, E., Palau, F., Espinos, C., and Galindo, M.I. (2015). Evolutionary History of the Smyd Gene Family in Metazoans: A Framework to Identify the Orthologs of Human Smyd Genes in Drosophila and Other Animal Species. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134106"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0968-0004(03)00090-2","article-title":"Many paths to methyltransfer: A chronicle of convergence","volume":"28","author":"Schubert","year":"2003","journal-title":"Trends Biochem. Sci."},{"key":"ref_16","unstructured":"(2025, August 22). Ensemble of Gene Set Enrichment Analyses Online. Available online: https:\/\/useast.ensembl.org\/Homo_sapiens\/Gene\/Summary?db=core;g=ENSG00000135632;r=2:73214222-73227221."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13072-017-0115-7","article-title":"SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation","volume":"10","author":"Kidder","year":"2017","journal-title":"Epigenet. Chromatin"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Alshammari, E., Sobota, J., Yang, A., Li, C., and Yang, Z. (2022). Unique SMYD5 Structure Revealed by AlphaFold Correlates with Its Functional Divergence. Biomolecules, 12.","DOI":"10.3390\/biom12060783"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4438","DOI":"10.1093\/nar\/gkr019","article-title":"Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding","volume":"39","author":"Xu","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1093\/jmcb\/mjr025","article-title":"Proteomic analyses of the SMYD family interactomes identify HSP90 as a novel target for SMYD2","volume":"3","author":"Lanouette","year":"2011","journal-title":"J. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Choudhury, N.R., Heikel, G., Trubitsyna, M., Kubik, P., Nowak, J.S., Webb, S., Granneman, S., Spanos, C., Rappsilber, J., and Castello, A. (2017). RNA-binding activity of TRIM25 is mediated by its PRY\/SPRY domain and is required for ubiquitination. BMC Biol., 15.","DOI":"10.1186\/s12915-017-0444-9"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/j.cell.2012.04.031","article-title":"Insights into RNA biology from an atlas of mammalian mRNA-binding proteins","volume":"149","author":"Castello","year":"2012","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"9185","DOI":"10.1128\/MCB.01529-06","article-title":"Profile of histone lysine methylation across transcribed mammalian chromatin","volume":"26","author":"Vakoc","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3542","DOI":"10.1038\/s41467-020-17237-x","article-title":"Structural snapshots of human pre-60S ribosomal particles before and after nuclear export","volume":"11","author":"Liang","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1111\/j.1432-1033.1997.00786.x","article-title":"Post-translational processing of rat ribosomal proteins. Ubiquitous methylation of Lys22 within the zinc-finger motif of RL40 (carboxy-terminal extension protein 52) and tissue-specific methylation of Lys4 in RL29","volume":"246","author":"Williamson","year":"1997","journal-title":"Eur. J. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/s41586-023-05908-w","article-title":"mRNA decoding in human is kinetically and structurally distinct from bacteria","volume":"617","author":"Holm","year":"2023","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1006\/jmbi.1999.2933","article-title":"Direct evidence that HIV-1 Tat stimulates RNA polymerase II carboxyl-terminal domain hyperphosphorylation during transcriptional elongation","volume":"290","author":"Isel","year":"1999","journal-title":"J. Mol. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29157","DOI":"10.1038\/srep29157","article-title":"Smyd5 plays pivotal roles in both primitive and definitive hematopoiesis during zebrafish embryogenesis","volume":"6","author":"Fujii","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6729","DOI":"10.1158\/0008-5472.CAN-17-0828","article-title":"SMYD5 controls heterochromatin and chromosome integrity during embryonic stem cell differentiation","volume":"77","author":"Kidder","year":"2017","journal-title":"Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e21686","DOI":"10.1096\/fj.202100183R","article-title":"Copper ions impair zebrafish skeletal myofibrillogenesis via epigenetic regulation","volume":"35","author":"Jin","year":"2021","journal-title":"FASEB J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.gene.2018.11.046","article-title":"The Kdm\/Kmt gene families in the self-fertilizing mangrove rivulus fish, Kryptolebias marmoratus, suggest involvement of histone methylation machinery in development and reproduction","volume":"687","author":"Fellous","year":"2019","journal-title":"Gene"},{"key":"ref_32","first-page":"3851","article-title":"Expression patterns and the prognostic value of the SMYD family members in human breast carcinoma using integrative bioinformatics analysis","volume":"17","author":"Song","year":"2019","journal-title":"Oncol. Lett."},{"key":"ref_33","first-page":"2219","article-title":"Comprehensive analysis of histone modification-associated genes on differential gene expression and prognosis in gastric cancer","volume":"18","author":"Meng","year":"2019","journal-title":"Exp. Ther. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"113076","DOI":"10.1016\/j.yexcr.2022.113076","article-title":"SMYD5 acts as a potential biomarker for hepatocellular carcinoma","volume":"414","author":"Chi","year":"2022","journal-title":"Exp. Cell Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Hu, M., Chen, S., Zhen, Y., Wang, X., Zhong, Y., Liang, X., Chong, C.M., and Zhong, H.J. (2025). SMYD5-BRD4 Interaction Drives Hepatocellular Carcinoma Progression: A Combined in Silico and Experimental Analysis. Pharmaceuticals, 18.","DOI":"10.3390\/ph18081105"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.molcel.2017.07.025","article-title":"The Short Isoform of BRD4 Promotes HIV-1 Latency by Engaging Repressive SWI\/SNF Chromatin-Remodeling Complexes","volume":"67","author":"Conrad","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"100067","DOI":"10.1016\/j.mocell.2024.100067","article-title":"Negative regulation of SH2B3 by SMYD5 controls epithelial-mesenchymal transition in lung cancer","volume":"47","author":"Tae","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Erdem, J.S., Zavodna, T., Ervik, T.K., Skare, O., Hron, T., Anmarkrud, K.H., Kusnierczyk, A., Catalan, J., Ellingsen, D.G., and Topinka, J. (2023). High aspect ratio nanomaterial-induced macrophage polarization is mediated by changes in miRNA levels. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1111123"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbrc.2021.02.073","article-title":"Sperm chromatin-condensing protamine enhances SMYD5 thermal stability","volume":"550","author":"Zhang","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.bbagrm.2013.08.004","article-title":"Chromatin dynamics during spermiogenesis","volume":"1839","author":"Rathke","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nature08162","article-title":"Distinctive chromatin in human sperm packages genes for embryo development","volume":"460","author":"Hammoud","year":"2009","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"114554","DOI":"10.1016\/j.celrep.2024.114554","article-title":"SMYD5 is a regulator of the mild hypothermia response","volume":"43","author":"Rafnsdottir","year":"2024","journal-title":"Cell Rep."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/j.jcmgh.2022.05.006","article-title":"Epithelial SMYD5 Exaggerates IBD by Down-regulating Mitochondrial Functions via Post-Translational Control of PGC-1alpha Stability","volume":"14","author":"Hou","year":"2022","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1056\/NEJMra0804647","article-title":"Inflammatory bowel disease","volume":"361","author":"Abraham","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/s11658-025-00707-9","article-title":"Novel regulation mechanism of histone methyltransferase SMYD5 in rheumatoid arthritis","volume":"30","author":"Xiao","year":"2025","journal-title":"Cell Mol. Biol. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1016\/S0140-6736(16)30173-8","article-title":"Rheumatoid arthritis","volume":"388","author":"Smolen","year":"2016","journal-title":"Lancet"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1136\/annrheumdis-2021-222021","article-title":"Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?","volume":"81","author":"Nemeth","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","article-title":"Fibroblast-like synoviocytes: Key effector cells in rheumatoid arthritis","volume":"233","author":"Bartok","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"30710","DOI":"10.1021\/acsomega.2c00984","article-title":"Histone H4K20 Trimethylation Is Decreased in Murine Models of Heart Disease","volume":"7","author":"Hickenlooper","year":"2022","journal-title":"ACS Omega"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2578553","DOI":"10.1080\/15592294.2025.2578553","article-title":"Expression profiles of histone H4K20 methylation and its associated enzymes in mouse cardiac disease and human heart failure","volume":"20","author":"Hickenlooper","year":"2025","journal-title":"Epigenetics"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/s41380-023-02403-6","article-title":"Placental transcriptomic signatures of prenatal and preconceptional maternal stress","volume":"29","author":"Baker","year":"2024","journal-title":"Mol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.cophys.2017.10.001","article-title":"The Smyd Family of Methyltransferases: Role in Cardiac and Skeletal Muscle Physiology and Pathology","volume":"1","author":"Tracy","year":"2018","journal-title":"Curr. Opin. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Wang, Z., Schwartz, R.J., Liu, J., Sun, F., Li, Q., and Ma, Y. (2021). Smyd1 Orchestrates Early Heart Development Through Positive and Negative Gene Regulation. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.654682"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E7871","DOI":"10.1073\/pnas.1800680115","article-title":"Histone methyltransferase Smyd1 regulates mitochondrial energetics in the heart","volume":"115","author":"Warren","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","first-page":"732.12","article-title":"Smyd5 Regulates Hypertropic Growth in the Heart","volume":"30","author":"Anderson","year":"2016","journal-title":"FASEB J. Physiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5884\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T04:25:45Z","timestamp":1783052745000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/5884"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,30]]},"references-count":55,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27135884"],"URL":"https:\/\/doi.org\/10.3390\/ijms27135884","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,30]]}}}