Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection

Introduction: Peripheral blood (PB) molecular patterns characterizing the different effector immune pathways driving distinct kidney rejection types remain to be fully elucidated. We hypothesized that transcriptome analysis using RNA sequencing (RNAseq) in samples of kidney transplant patients would...

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Autores: Pineda, Silvia, Sur, Swastika, Sigdel, Tara, Nguyen, Mark, Crespo, Elena, Torija Recasens, Alba, Meneghini, Maria, Gomà, Montse, Sirota, Marina, Bestard Matamoros, Oriol, Sarwal, Minnie M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/174006
Acceso en línea:https://hdl.handle.net/2445/174006
Access Level:acceso abierto
Palabra clave:Trasplantament renal
Rebuig (Biologia)
Kidney transplantation
Graft rejection
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spelling Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft RejectionPineda, SilviaSur, SwastikaSigdel, TaraNguyen, MarkCrespo, ElenaTorija Recasens, AlbaMeneghini, MariaGomà, MontseSirota, MarinaBestard Matamoros, OriolSarwal, Minnie M.Trasplantament renalRebuig (Biologia)Kidney transplantationGraft rejectionIntroduction: Peripheral blood (PB) molecular patterns characterizing the different effector immune pathways driving distinct kidney rejection types remain to be fully elucidated. We hypothesized that transcriptome analysis using RNA sequencing (RNAseq) in samples of kidney transplant patients would enable the identification of unique protein-coding and noncoding genes that may be able to segregate different rejection phenotypes. Methods: We evaluated 37 biopsy-paired PB samples from the discovery cohort, with stable (STA), antibody-mediated rejection (AMR), and T cell-mediated rejection (TCMR) by RNAseq. Advanced machine learning tools were used to perform 3-way differential gene expression analysis to identify gene signatures associated with rejection. We then performed functional in silico analysis and validation by Fluidigm (San Francisco, CA) in 62 samples from 2 independent kidney transplant cohorts. Results: We found 102 genes (63 coding genes and 39 noncoding genes) associated with AMR (54 upregulated), TCMR (23 upregulated), and STA (25 upregulated) perfectly clustered with each rejection phenotype and highly correlated with main histologic lesions (r = 0.91). For the genes associated with AMR, we found enrichment in regulation of endoplasmic reticulum stress, adaptive immunity, and Ig class-switching. In the validation, we found that the SIGLEC17P pseudogene and 9 SIGLEC17P-related coding genes were highly expressed among AMR but not in TCMR and STA samples. Conclusions: This analysis identifies a critical gene signature in PB in kidney transplant patients undergoing AMR, sufficient to differentiate them from patients with TCMR and immunologically quiescent kidney allografts. Our findings provide the basis for new studies dissecting the role of noncoding genes in the pathophysiology of kidney allograft rejection and their potential value as noninvasive biomarkers of the rejection process.Elsevier Science Inc2021202120202021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion16 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/174006Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.ekir.2020.07.023Kidney International Reports, 2020, Vol. 5, Issue 10, P. 1706-1721https://doi.org/10.1016/j.ekir.2020.07.023cc by-nc-nd (c) Pineda, Silvia et al., 2020http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1740062026-05-29T05:05:01Z
dc.title.none.fl_str_mv Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
title Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
spellingShingle Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
Pineda, Silvia
Trasplantament renal
Rebuig (Biologia)
Kidney transplantation
Graft rejection
title_short Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
title_full Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
title_fullStr Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
title_full_unstemmed Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
title_sort Peripheral Blood RNA Sequencing Unravels a Differential Signature of Coding and Noncoding Genes by Types of Kidney Allograft Rejection
dc.creator.none.fl_str_mv Pineda, Silvia
Sur, Swastika
Sigdel, Tara
Nguyen, Mark
Crespo, Elena
Torija Recasens, Alba
Meneghini, Maria
Gomà, Montse
Sirota, Marina
Bestard Matamoros, Oriol
Sarwal, Minnie M.
author Pineda, Silvia
author_facet Pineda, Silvia
Sur, Swastika
Sigdel, Tara
Nguyen, Mark
Crespo, Elena
Torija Recasens, Alba
Meneghini, Maria
Gomà, Montse
Sirota, Marina
Bestard Matamoros, Oriol
Sarwal, Minnie M.
author_role author
author2 Sur, Swastika
Sigdel, Tara
Nguyen, Mark
Crespo, Elena
Torija Recasens, Alba
Meneghini, Maria
Gomà, Montse
Sirota, Marina
Bestard Matamoros, Oriol
Sarwal, Minnie M.
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Trasplantament renal
Rebuig (Biologia)
Kidney transplantation
Graft rejection
topic Trasplantament renal
Rebuig (Biologia)
Kidney transplantation
Graft rejection
description Introduction: Peripheral blood (PB) molecular patterns characterizing the different effector immune pathways driving distinct kidney rejection types remain to be fully elucidated. We hypothesized that transcriptome analysis using RNA sequencing (RNAseq) in samples of kidney transplant patients would enable the identification of unique protein-coding and noncoding genes that may be able to segregate different rejection phenotypes. Methods: We evaluated 37 biopsy-paired PB samples from the discovery cohort, with stable (STA), antibody-mediated rejection (AMR), and T cell-mediated rejection (TCMR) by RNAseq. Advanced machine learning tools were used to perform 3-way differential gene expression analysis to identify gene signatures associated with rejection. We then performed functional in silico analysis and validation by Fluidigm (San Francisco, CA) in 62 samples from 2 independent kidney transplant cohorts. Results: We found 102 genes (63 coding genes and 39 noncoding genes) associated with AMR (54 upregulated), TCMR (23 upregulated), and STA (25 upregulated) perfectly clustered with each rejection phenotype and highly correlated with main histologic lesions (r = 0.91). For the genes associated with AMR, we found enrichment in regulation of endoplasmic reticulum stress, adaptive immunity, and Ig class-switching. In the validation, we found that the SIGLEC17P pseudogene and 9 SIGLEC17P-related coding genes were highly expressed among AMR but not in TCMR and STA samples. Conclusions: This analysis identifies a critical gene signature in PB in kidney transplant patients undergoing AMR, sufficient to differentiate them from patients with TCMR and immunologically quiescent kidney allografts. Our findings provide the basis for new studies dissecting the role of noncoding genes in the pathophysiology of kidney allograft rejection and their potential value as noninvasive biomarkers of the rejection process.
publishDate 2020
dc.date.none.fl_str_mv 2020
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/174006
url https://hdl.handle.net/2445/174006
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.ekir.2020.07.023
Kidney International Reports, 2020, Vol. 5, Issue 10, P. 1706-1721
https://doi.org/10.1016/j.ekir.2020.07.023
dc.rights.none.fl_str_mv cc by-nc-nd (c) Pineda, Silvia et al., 2020
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Pineda, Silvia et al., 2020
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 16 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier Science Inc
publisher.none.fl_str_mv Elsevier Science Inc
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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