Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor

查看全文 作　　者：Keith Al-[1,2]Hasani;Ishant [1,2]Khurana;Lina [3]Mariana;Thomas [3]Loudovaris;Scott [1,2]Maxwell;[1,2,4]K.N.Harikrishnan;Jun [1,2]Okabe;Mark [1]ECooper;Assam El-[1,2,4,5,6,7,8]Osta

机构地区：[1]Department of Diabetes,Central Clinical School,Monash University,Melbourne,Victoria 3004,Australia;[2]Epigenetics in Human Health and Disease Laboratory,Central Clinical School,Monash University,Melbourne,Victoria 3004,Australia;[3]Immunology and Diabetes Unit,St Vincent’s Institute of Medical Research,Fitzroy,Victoria,Australia;[4]Department of Clinical Pathology,The University of Melbourne,Parkville,Victoria,Australia;[5]Department of Medicine and Therapeutics,The Chinese University of Hong Kong,Sha Tin,Hong Kong SAR;[6]Hong Kong Institute of Diabetes and Obesity,Prince of Wales Hospital,The Chinese University of Hong Kong,3/F Lui Che Woo Clinical Sciences Building,30-32 Ngan Shing Street,Sha Tin,Hong Kong SAR;[7]Li Ka Shing Institute of Health Sciences,The Chinese University of Hong Kong,Sha Tin,Hong Kong SAR;[8]Faculty of Health,Department of Technology,Biomedical Laboratory Science,University College Copenhagen,Copenhagen,Denmark

出　　处：《Signal Transduction and Targeted Therapy》索引2022年第7卷第8期,共9页

基　　金：A.E-O.is a National Health and Medical Research Council(NHMRC)Senior Research Fellow(1154650);acknowledges grant funding(2003401,1113188);M.E.C.acknowledges NHMRC(1175760);supported by an Innovation Grant from JDRF International(Grant#1-INO-2022-1123-A-N)。 摘　　要：Type 1 diabetes(T1D)is an autoimmune disease that selectively destroys insulin-producingβ-cells in the pancreas.An unmet need in diabetes management,current therapy is focussed on transplantation.While the reprogramming of progenitor cells into functional insulin-producingβ-cells has also been proposed this remains controversial and poorly understood.The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation.After the death of a 13-year-old girl with established insulin-dependent T1D,pancreatic cells were harvested in an effort to restore and understand exocrine competence.The pancreas showed classic silencing ofβ-cell progenitor genes with barely detectable insulin(Ins)transcript.GSK126,a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of coreβ-cell markers and ductal progenitor genes.GSK126 also reinstated Ins gene expression despite absoluteβ-cell destruction.These studies show the refractory nature of chromatin characterises exocrine suppression influencingβ-cell plasticity.Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population. 关键词：EZH2 PROGENITOR DONOR

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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor

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