TY - JOUR
T1 - Differential expression of long noncoding RNAs during cardiac allograft rejection
AU - Gu, Guangxiang
AU - Huang, Yingjuan
AU - Wu, Chenglin
AU - Guo, Zhiyong
AU - Ma, Yi
AU - Xia, Qiang
AU - Awasthi, Amit
AU - He, Xiaoshun
N1 - Funding Information:
This study was supported by the National High Technology Research and Development Program of China (863 Program) (2012AA021007 & 2012AA021008), the National Natural Science Foundation of China (81102244, 81102245, 81170448, 81373156 and 81471583), the Special Fund for Science Research by Ministry of Health (201302009), the Key Clinical Specialty Construction Project of National Health and Family Planning Commission of the People's Republic of China, the Guangdong Provincial Key Laboratory Construction Projection on Organ Donation and Transplant Immunology (2013A061401007), Pearl River Nova Program of Guangzhou, and Guangdong Provincial Natural Science Funds for Distinguished Young Scholars. AA was supported by DBT-Wellcome Trust intermediate fellowship (IA/I/12/1/500524).
Publisher Copyright:
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
PY - 2017/1
Y1 - 2017/1
N2 - 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 transplantationmodel.We screened the differentially expressed lncRNAs andmRNAs, 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 andmRNA, which are differentially expressed during transplant rejection inmouse 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 lncRNAA930015D03Rik 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
AB - 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 transplantationmodel.We screened the differentially expressed lncRNAs andmRNAs, 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 andmRNA, which are differentially expressed during transplant rejection inmouse 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 lncRNAA930015D03Rik 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
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U2 - 10.1097/TP.0000000000001463
DO - 10.1097/TP.0000000000001463
M3 - Article
C2 - 27575691
AN - SCOPUS:84984697481
VL - 101
SP - 83
EP - 91
JO - Transplantation
JF - Transplantation
SN - 0041-1337
IS - 1
ER -