title: Differential Expression of Long Noncoding RNAs During Cardiac Allograft Rejection.
abstract: BACKGROUND
  Organ transplantation is the most effective treatment for end-stage diseases. Although transplant rejection is the major restriction in successful long-lasting graft survival, induction of sustainable immune tolerance against transplant is one of the major goals in transplantation to enable long-term graft survival. Although various mechanisms have been suggested that induce immune tolerance during transplantation, the roles of long noncoding RNAs (lncRNAs), which modulate gene expression and regulate innate and adaptive immune responses, are not clearly understood in transplantation. Here, we described the role of 2 essential lncRNAs, lncRNA-A930015D03Rik and mouselincRNA1055, in regulating T helper 1 (Th1) response in graft rejection.
  
  
  METHODS
  To understand the gene expression and lncRNA profile during transplantation, we performed microarray to profile lncRNA and messenger (m)RNA of the heart graft and graft-infiltrating lymphocytes (GILs) in allogeneic and syngeneic mouse heart transplantation model. We screened the differentially expressed lncRNAs and mRNAs, and generated the network of lncRNA-mRNA coexpression and computationally predicted their association in transplantation. We further validated the selected T cell related lncRNAs by qPCR, which we identified in gene set enrichment analysis. The functional validation of these lncRNAs in the regulation of Th1 response in transplantation was performed by short hairpin RNA-mediated inhibition.
  
  
  RESULTS
  We established a profile of lncRNA and mRNA, which are differentially expressed during transplant rejection in mouse model of heart transplant. Consistent with the microarray results, we have confirmed and validated the expression of 7 lncRNA by qPCR. The lncRNA-A930015D03Rik and mouselincRNA1055 were highly expressed in allogeneic heart graft and GILs. We further identified that expression of IL-12Rβ1 is strongly correlated with lncRNA-A930015D03Rik and mouselincRNA1055 in GILs. Further analysis revealed the association of lncRNA-A930015D03Rik and mouselincRNA1055 with Th1 cells in graft rejection. The functions of lncRNA-A930015D03Rik and mouselincRNA1055 were validated in differentiation of Th1 cells by knocking down their expression. Inhibition of lncRNA-A930015D03Rik and mouselincRNA1055 substantially suppressed the expression of IL-12Rβ1 and IFN-γ induction in Th1 cells.
  
  
  CONCLUSIONS
  Our results provide a detailed profile of lncRNAs that may regulate immune response and graft outcomes. Our data not only suggest the involvement of lncRNA-A930015D03Rik and mouselincRNA1055 in the regulation of Th1 cells response during graft rejection but also identify them as novel biomarkers for subclinical graft rejection.
authors: 1 Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. 2 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 3 Traditional Chinese Medicine Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 4 Translational Health Science & Technology Institute, Faridabad, India.
authors: Guangxiang
authors: G
authors: Gu
authors: Yingjuan
authors: Y
authors: Huang
authors: Chenglin
authors: C
authors: Wu
authors: Zhiyong
authors: Z
authors: Guo
authors: Yi
authors: Y
authors: Ma
authors: Qiang
authors: Q
authors: Xia
authors: Amit
authors: A
authors: Awasthi
authors: Xiaoshun
authors: X
authors: He
mesh_terms: D064591:Allografts; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D005819:Genetic Markers; D006084:Graft Rejection / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D016027:Heart Transplantation / Q000009:adverse effects*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D005819:Genetic Markers; C508440:Il12rb1 protein, mouse; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12; D007371:Interferon-gamma