{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T22:30:04Z","timestamp":1790721004150,"version":"4.1.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T00:00:00Z","timestamp":1604275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease characterized by immune-mediated destruction of pancreatic beta-cells. Multiple microRNAs (miRNAs) have been implicated in T1DM pathogenesis. Although histone deacetylase 3 (HDAC3) has been reported to be involved in T1DM, the underlying mechanisms remain to be further elucidated. This study was designed to investigate the potential regulatory role of <jats:italic>Hdac3<\/jats:italic> on T1DM progression. The expression of <jats:italic>miR-296-5p<\/jats:italic> and B-cell leukemia-XL (BCL-XL) was determined using RT-qPCR and Western blot assay in peripheral blood mononuclear cells (PBMCs) of patients with T1DM, tumor necrosis factor-\u03b1 (TNF-\u03b1)- and cycloheximide (CHX)-induced cell model, and streptozotocin (STZ)-induced rat model. The binding affinity between <jats:italic>miR-296-5p<\/jats:italic> and <jats:italic>Bcl-xl<\/jats:italic> was verified by using dual-luciferase reporter gene assay, and the binding between <jats:italic>Hdac3<\/jats:italic> and the promoter region of <jats:italic>miR-296-5p<\/jats:italic> was validated using chromatin immunoprecipitation assay. Western blot analysis and flow cytometry were conducted to assess the apoptotic events of lymphocytes. <jats:italic>miR-296-5p<\/jats:italic> expression was downregulated while BCL-XL expression was upregulated in PBMCs of patients with T1DM. An adverse correlation was identified between <jats:italic>miR-296-5p<\/jats:italic> and <jats:italic>Bcl-xl<\/jats:italic> in mouse TE15 B lymphocytes. <jats:italic>Bcl-xl<\/jats:italic> was further validated to be targeted and negatively regulated by <jats:italic>miR-296-5p<\/jats:italic> in 293 T cells. <jats:italic>Hdac3<\/jats:italic> inhibited <jats:italic>miR-296-5p<\/jats:italic> expression by binding to its promoter region. The effects of overexpressed <jats:italic>Hdac3<\/jats:italic> on lymphocyte apoptosis was counterweighed <jats:italic>via<\/jats:italic> downregulation of <jats:italic>Bcl-xl<\/jats:italic> or upregulation of <jats:italic>miR-296-5p<\/jats:italic>, the mechanism of which was further validated in a rat model of DM. Taken together, the <jats:italic>Hdac3<\/jats:italic>-mediated upregulation of <jats:italic>Bcl-xl via<\/jats:italic> inhibiting <jats:italic>miR-296-5p<\/jats:italic> promoter activity enhanced the anti-apoptotic capacity of lymphocytes to accelerate the occurrence of T1DM.<\/jats:p>","DOI":"10.3389\/fgene.2020.536854","type":"journal-article","created":{"date-parts":[[2020,11,2]],"date-time":"2020-11-02T05:01:15Z","timestamp":1604293275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["Histone Deacetylase 3 Aggravates Type 1 Diabetes Mellitus by Inhibiting Lymphocyte Apoptosis Through the microRNA-296-5p\/Bcl-xl Axis"],"prefix":"10.3389","volume":"11","author":[{"given":"Qibo","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guanghua","family":"Che","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchang","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,11,2]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1089\/dna.2014.2352","article-title":"Apoptosis of beta cells in diabetes mellitus","volume":"33","author":"Anuradha","year":"2014","journal-title":"DNA Cell Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/j.jphotobiol.2016.05.027","article-title":"The role of photobiomodulation on gene expression of cell adhesion molecules in diabetic wounded fibroblasts in vitro","volume":"161","author":"Ayuk","year":"2016","journal-title":"J. Photochem. Photobiol. B"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"2895","DOI":"10.1161\/CIRCULATIONAHA.118.035525","article-title":"Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus","volume":"138","author":"Bjornstad","year":"2018","journal-title":"Circulation"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e0185441","DOI":"10.1371\/journal.pone.0185441","article-title":"Class II and IV HDACs function as inhibitors of osteoclast differentiation","volume":"12","author":"Blixt","year":"2017","journal-title":"PLoS One"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s12933-015-0262-8","article-title":"Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice","volume":"14","author":"Chen","year":"2015","journal-title":"Cardiovasc. Diabetol."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1016\/j.chembiol.2012.05.010","article-title":"Inhibition of histone deacetylase 3 protects beta cells from cytokine-induced apoptosis","volume":"19","author":"Chou","year":"2012","journal-title":"Chem. Biol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"378","DOI":"10.2119\/molmed.2011.00021","article-title":"Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus","volume":"17","author":"Christensen","year":"2011","journal-title":"Mol. Med."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1823","DOI":"10.1007\/s00125-019-4942-x","article-title":"Early-life factors contributing to type 1 diabetes","volume":"62","author":"Craig","year":"2019","journal-title":"Diabetologia"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1007\/s00125-016-4142-x","article-title":"Type 1 diabetes mellitus and risk of incident epilepsy: a population-based, open-cohort study","volume":"60","author":"Dafoulas","year":"2017","journal-title":"Diabetologia"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"5291","DOI":"10.1038\/s41467-019-13180-8","article-title":"Deletion of intestinal Hdac3 remodels the lipidome of enterocytes and protects mice from diet-induced obesity","volume":"10","author":"Davalos-Salas","year":"2019","journal-title":"Nat. Commun."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"434","DOI":"10.2337\/dc15-1765","article-title":"Altered peripheral B-lymphocyte subsets in type 1 diabetes and latent autoimmune diabetes in adults","volume":"39","author":"Deng","year":"2016","journal-title":"Diabetes Care"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1111\/j.1365-2249.2012.04583.x","article-title":"Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation","volume":"168","author":"de Oliveira","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"586","DOI":"10.1177\/1535370218761662","article-title":"Targeting dysfunctional beta-cell signaling for the potential treatment of type 1 diabetes mellitus","volume":"243","author":"Fenske","year":"2018","journal-title":"Exp. Biol. Med."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1093\/eurheartj\/ehq499","article-title":"Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus","volume":"32","author":"Giubilato","year":"2011","journal-title":"Eur. Heart J."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1002\/dmrr.559","article-title":"Role of histone and transcription factor acetylation in diabetes pathogenesis","volume":"21","author":"Gray","year":"2005","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"669","DOI":"10.2217\/epi.15.20","article-title":"The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention","volume":"7","author":"Khan","year":"2015","journal-title":"Epigenomics"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"863","DOI":"10.1007\/s12272-020-01252-z","article-title":"Ferulic acid protects cardiomyocytes from TNF-alpha\/cycloheximide-induced apoptosis by regulating autophagy","volume":"43","author":"Li","year":"","journal-title":"Arch. Pharm. Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"969","DOI":"10.2147\/DMSO.S207021","article-title":"Identification of dynamic molecular networks in peripheral blood mononuclear cells in type 1 diabetes mellitus","volume":"12","author":"Li","year":"2019","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"104547","DOI":"10.1016\/j.phrs.2019.104547","article-title":"Bcl-XL: a multifunctional anti-apoptotic protein","volume":"151","author":"Li","year":"","journal-title":"Pharmacol. Res."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"e3104","DOI":"10.1002\/dmrr.3104","article-title":"MicroRNA-296-5p promotes healing of diabetic wound by targeting sodium-glucose transporter 2 (SGLT2)","volume":"35","author":"Liu","year":"2019","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"170","DOI":"10.2337\/db11-1464","article-title":"Bcl-2 and Bcl-xL suppress glucose signaling in pancreatic beta-cells","volume":"62","author":"Luciani","year":"2013","journal-title":"Diabetes"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.retram.2019.08.001","article-title":"Role of HDAC inhibitors in diabetes mellitus","volume":"68","author":"Makkar","year":"2019","journal-title":"Curr. Res. Transl. Med."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1002\/1878-0261.12536","article-title":"Methylation-associated miR-193b silencing activates master drivers of aggressive prostate cancer","volume":"13","author":"Mazzu","year":"2019","journal-title":"Mol. Oncol."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"209","DOI":"10.2217\/epi.14.11","article-title":"Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics","volume":"6","author":"Meier","year":"2014","journal-title":"Epigenomics"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.3390\/molecules24061047","article-title":"Role of natural products in modulating histone deacetylases in cancer","volume":"24","author":"Merarchi","year":"2019","journal-title":"Molecules"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.2174\/1568026619666190227221507","article-title":"An overview of HDAC inhibitors and their synthetic routes","volume":"19","author":"Peng","year":"2019","journal-title":"Curr. Top. Med. Chem."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.gene.2014.01.075","article-title":"MicroRNA expression profiling and functional annotation analysis of their targets in patients with type 1 diabetes mellitus","volume":"539","author":"Takahashi","year":"2014","journal-title":"Gene"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s41586-018-0620-2","article-title":"The human gut microbiome in early-onset type 1 diabetes from the TEDDY study","volume":"562","author":"Vatanen","year":"2018","journal-title":"Nature"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.devcel.2015.12.031","article-title":"HDAC3-dependent epigenetic pathway controls lung alveolar epithelial cell remodeling and spreading via miR-17-92 and TGF-beta signaling regulation","volume":"36","author":"Wang","year":"2016","journal-title":"Dev. Cell"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.bbrc.2017.06.196","article-title":"Decreased expression of miR-150, miR146a and miR424 in type 1 diabetic patients: association with ongoing islet autoimmunity","volume":"498","author":"Wang","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1053\/j.gastro.2018.04.017","article-title":"Disruption of epithelial HDAC3 in intestine prevents diet-induced obesity in mice","volume":"155","author":"Whitt","year":"2018","journal-title":"Gastroenterology"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1841","DOI":"10.1042\/CS20170064","article-title":"Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1\/2 pathway","volume":"131","author":"Xu","year":"2017","journal-title":"Clin. Sci."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1016\/j.ejmech.2018.10.072","article-title":"Therapeutic potential of selective histone deacetylase 3 inhibition","volume":"162","author":"Zhang","year":"","journal-title":"Eur. J. Med. Chem."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"9071297","DOI":"10.1155\/2019\/9071297","article-title":"CRISPR\/Cas9 knockout of Bak mediates Bax translocation to mitochondria in response to TNFalpha\/CHX-induced apoptosis","volume":"2019","author":"Zhang","year":"","journal-title":"Biomed. Res. Int."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"E150","DOI":"10.1152\/ajpendo.00465.2017","article-title":"HDAC3 inhibition in diabetic mice may activate Nrf2 preventing diabetes-induced liver damage and FGF21 synthesis and secretion leading to aortic protection","volume":"315","author":"Zhang","year":"2018","journal-title":"Am. J. Physiol. Endocrinol. Metab."}],"updated-by":[{"DOI":"10.3389\/fgene.2021.715061","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2021,9,22]],"date-time":"2021-09-22T00:00:00Z","timestamp":1632268800000}}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2020.536854\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T01:35:25Z","timestamp":1633052125000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2020.536854\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,2]]},"references-count":35,"alternative-id":["10.3389\/fgene.2020.536854"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2020.536854","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fgene.2021.715061","asserted-by":"object"}]},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,2]]},"article-number":"536854"}}