{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T19:24:06Z","timestamp":1773343446480,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Accelerated cell apoptosis with dysregulated long noncoding RNAs is the crucial pathogenesis in lupus nephritis (LN). Pro-apoptotic lincRNA-p21 was studied in LN patients, cell lines with lentivirus-mediated overexpression and CRISPR interference (CRISPRi)-conducted repression, and a mouse model. Clinical samples were from patients and age\/sex-matched controls. Expression of lincRNA-p21 and endogenous RNA target miR-181a, were examined in mononuclear and urine cells. Guide RNA sequences targeting lincRNA-p21 were cloned into CRISPRi with dCas9\/ Kr\u00fcppel-associated box (KRAB) domain. LincRNA-p21-silened transfectants were investigated for apoptosis and miR-181a expression. LincRNA-p21-overexpressed cells were evaluated for apoptosis and p53-related down-stream molecules. Balb\/C mice were injected with pristane to induce LN and examined for apoptosis and lincRNA-p21. Higher lincRNA-p21 levels were found in LN mononuclear and urine cells, positively correlated with activity. There were lower miR-181a levels in LN mononuclear cells, negatively correlated with activity. Doxorubicin-induced apoptotic cells had up-regulated lincRNA-p21 levels. CRISPRi with dCas9\/KARA domain showed efficient repression ability on transcription initiation\/elongation. CRISPRi-conducted lincRNA-p21-silenced transfectants displayed reduced apoptosis with up-regulated miR-181a levels, whereas lentivirus-mediated lincRNA-p21-overexpressed cells revealed enhanced apoptosis with up-regulated downstream PUMA\/Bax expression. LN mice had glomerular apoptosis with progressive increased lincRNA-p21 levels. Our results demonstrate up-regulated lincRNA-p21 expression in LN, implicating a potential diagnostic marker and therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms22010301","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T09:35:23Z","timestamp":1609320923000},"page":"301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Up-Regulated Expression of Pro-Apoptotic Long Noncoding RNA lincRNA-p21 with Enhanced Cell Apoptosis in Lupus Nephritis"],"prefix":"10.3390","volume":"22","author":[{"given":"Yi-Cheng","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan 70403, Taiwan"},{"name":"Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pin-Yu","family":"Kuo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chi","family":"Chou","sequence":"additional","affiliation":[{"name":"Biomedical Translation Research Center, Academia Sinica, Taipei 11529, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao-Earn","family":"Chong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan 70403, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Tung","family":"Hsieh","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mei-Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7821-9406","authenticated-orcid":false,"given":"Chao-Liang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2449-8547","authenticated-orcid":false,"given":"Ai-Li","family":"Shiau","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrong-Reen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Cheng Kung University Medical College and Hospital, Tainan 70403, Taiwan"},{"name":"Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan 70101, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/nrneph.2017.85","article-title":"Redefining lupus nephritis: Clinical implications of pathophysiologic subtypes","volume":"13","author":"Yu","year":"2017","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1159\/000368581","article-title":"Lupus nephritis: From pathogenesis to targets for biologic treatment","volume":"128","author":"Liu","year":"2014","journal-title":"Nephron. Clin. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.clim.2016.08.010","article-title":"Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis","volume":"185","author":"Mistry","year":"2017","journal-title":"Clin. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/cei.13041","article-title":"Self-dsDNA in the pathogenesis of systemic lupus erythematosus","volume":"191","author":"Bai","year":"2018","journal-title":"Clin. Exp. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1177\/0961203309103152","article-title":"Increased T-lymphocyte apoptosis in lupus correlates with disease activity and may be responsible for reduced T-cell frequency: A cross-sectional and longitudinal study","volume":"18","author":"Dhir","year":"2009","journal-title":"Lupus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrm.2017.104","article-title":"The functions and unique features of long intergenic non-coding RNA","volume":"19","author":"Ransohoff","year":"2018","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.4110\/in.2019.19.e4","article-title":"Potential implications of long noncoding RNAs in autoimmune diseases","volume":"19","author":"Hur","year":"2019","journal-title":"Immune Netw."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Taheri, M., Eghtedarian, R., Dinger, M.E., and Ghafouri-Fard, S. (2020). Exploring the role of non-coding RNAs in the pathophysiology of systemic lupus erythematosus. Biomolecules, 10.","DOI":"10.3390\/biom10060937"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000074428","article-title":"Relationship of p53 with other oncogenes, cytokines and systemic lupus erythematosus activity","volume":"24","author":"Miret","year":"2003","journal-title":"Tumor Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13578-020-00445-9","article-title":"An update on long intergenic noncoding RNA p21: A regulatory molecule with various significant functions in cancer","volume":"10","author":"Amirinejad","year":"2020","journal-title":"Cell. Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/j.cell.2010.06.040","article-title":"A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response","volume":"142","author":"Huarte","year":"2010","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1002\/art.38805","article-title":"Methotrexate inhibits NF-\u03baB activity via long intergenic (noncoding) RNA-p21 induction","volume":"66","author":"Spurlock","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1016\/j.cell.2011.07.014","article-title":"A ceRNA hypothesis: The Rosetta Stone of a hidden RNA language?","volume":"146","author":"Salmena","year":"2011","journal-title":"Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1002\/eji.201545487","article-title":"Cross-regulation between cytokine and microRNA pathways in T cells","volume":"45","author":"Amado","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_15","first-page":"351","article-title":"Expression signature of microRNA-181-a reveals its crucial role in the pathogenesis of paediatric systemic lupus erythematosus","volume":"29","author":"Lashine","year":"2011","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"24194","DOI":"10.3390\/ijms161024194","article-title":"Cytokines and microRNAs as candidate biomarkers for systemic lupus erythematosus","volume":"16","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1021\/acschembio.7b00657","article-title":"CRISPRi and CRISPRa screens in mammalian cells for precision biology and medicine","volume":"13","author":"Kampmann","year":"2018","journal-title":"ACS Chem. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1186\/gb-2003-4-10-231","article-title":"KRAB-containing zinc-finger repressor proteins","volume":"4","author":"Urrutia","year":"2003","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.cell.2007.03.008","article-title":"MiR-181a is an intrinsic modulator of T cell sensitivity and selection","volume":"129","author":"Li","year":"2007","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1186\/ar3251","article-title":"Abnormalities of T cell signaling in systemic lupus erythematosus","volume":"13","author":"Moulton","year":"2011","journal-title":"Arthritis Res. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e000260","DOI":"10.1136\/lupus-2018-000260","article-title":"TNF-\u03b1 and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus","volume":"5","author":"Idborg","year":"2018","journal-title":"Lupus Sci. Med."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Hadjicharalambous, M.R., and Lindsay, M.A. (2019). Long non-coding RNAs and the innate immune response. Noncoding RNA, 5.","DOI":"10.3390\/ncrna5020034"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1002\/art.40077","article-title":"Pathogenesis of diffuse alveolar hemorrhage in murine lupus","volume":"69","author":"Zhuang","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.4049\/jimmunol.152.7.3685","article-title":"Accelerated in vitro apoptosis of lymphocytes from patients with systemic lupus erythematosus","volume":"152","author":"Emlen","year":"1994","journal-title":"J. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.4049\/jimmunol.176.4.2095","article-title":"Accelerated macrophage apoptosis induces autoantibody formation and organ damage in systemic lupus erythematosus","volume":"176","author":"Denny","year":"2006","journal-title":"J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"255","DOI":"10.5301\/JN.2011.8451","article-title":"Increased apoptosis and expression of FasL, Bax and caspase-3 in human lupus nephritis class II and IV","volume":"25","author":"Cui","year":"2012","journal-title":"J. Nephrol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00762","DOI":"10.7554\/eLife.00762","article-title":"A mammalian pseudogene lncRNA at the interface of inflammation and anti-inflammatory therapeutics","volume":"2","author":"Rapicavoli","year":"2013","journal-title":"Elife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1097\/BOR.0000000000000412","article-title":"An update on lupus animal models","volume":"29","author":"Li","year":"2017","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.it.2009.06.003","article-title":"Induction of autoimmunity by pristane and other naturally occurring hydrocarbons","volume":"30","author":"Reeves","year":"2009","journal-title":"Trends Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.cell.2014.09.029","article-title":"Genome-scale CRISPR-mediated control of gene repression and activation","volume":"159","author":"Gilbert","year":"2014","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1038\/s41592-018-0048-5","article-title":"An enhanced CRISPR repressor for targeted mammalian gene regulation","volume":"15","author":"Yeo","year":"2018","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"13479","DOI":"10.18632\/oncotarget.7266","article-title":"Competing endogenous RNA networks in human cancer: Hypothesis, validation, and perspectives","volume":"7","author":"Yang","year":"2016","journal-title":"Oncotarget"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.coi.2019.07.003","article-title":"Mechanisms of action of low-dose IL-2 restoration therapies in SLE","volume":"61","author":"Papillion","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1136\/annrheumdis-2019-215396","article-title":"Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: A randomised, double-blind, placebo-controlled trial","volume":"79","author":"He","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1002\/art.1780400928","article-title":"Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus","volume":"40","author":"Hochberg","year":"1997","journal-title":"Arthritis Rheum."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Bonomini, F., Dos Santos, M., Veronese, F.V., and Rezzani, R. (2019). NLRP3 Inflammasome modulation by melatonin supplementation in chronic pristane-induced lupus nephritis. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143466"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2080","DOI":"10.1038\/nprot.2012.115","article-title":"Generation of human induced pluripotent stem cells from urine samples","volume":"7","author":"Zhou","year":"2012","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1007\/BF02623606","article-title":"Initiation and characterization of primary mouse kidney epithelial cultures","volume":"24","author":"Bell","year":"1988","journal-title":"In Vitro Cell Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1002\/art.39446","article-title":"Amelioration of experimental autoimmune arthritis through targeting synovial fibroblasts by the intra-articular delivery of microRNA-140-3p and -5p","volume":"68","author":"Peng","year":"2016","journal-title":"Arthritis Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"115413","DOI":"10.18632\/oncotarget.23268","article-title":"P53-derived hybrid peptides induce apoptosis of synovial fibroblasts in the rheumatoid joint","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/301\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:47:51Z","timestamp":1760179671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/1\/301"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,30]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22010301"],"URL":"https:\/\/doi.org\/10.3390\/ijms22010301","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,30]]}}}