Cargando…
Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion
Ribonuclease T2 gene (RNASET2) variants are associated in genome wide association studies (GWAS) with risk for several autoimmune diseases, including Crohn’s disease (CD). In T cells, a functional and biological relationship exists between TNFSF15-mediated enhancement of IFN−γ production, mucosal in...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709281/ https://www.ncbi.nlm.nih.gov/pubmed/36466822 http://dx.doi.org/10.3389/fimmu.2022.999155 |
_version_ | 1784841115671724032 |
---|---|
author | Biener-Ramanujan, Eva Rosier, Florian Coetzee, Simon G. McGovern, Dermot D. P. Hazelett, Dennis Targan, Stephan R. Gonsky, Rivkah |
author_facet | Biener-Ramanujan, Eva Rosier, Florian Coetzee, Simon G. McGovern, Dermot D. P. Hazelett, Dennis Targan, Stephan R. Gonsky, Rivkah |
author_sort | Biener-Ramanujan, Eva |
collection | PubMed |
description | Ribonuclease T2 gene (RNASET2) variants are associated in genome wide association studies (GWAS) with risk for several autoimmune diseases, including Crohn’s disease (CD). In T cells, a functional and biological relationship exists between TNFSF15-mediated enhancement of IFN−γ production, mucosal inflammation and RNASET2. Disease risk variants are associated with decreased mRNA expression and clinical characteristics of severe CD; however, functional classifications of variants and underlying molecular mechanisms contributing to pathogenesis remain largely unknown. In this study we demonstrate that allelic imbalance of RNASET2 disease risk variant rs2149092 is associated with transcriptional and post-transcriptional mechanisms regulating transcription factor binding, promoter-transactivation and allele-specific expression. RNASET2 mRNA expression decreases in response to multiple modes of T cell activation and recovers following elimination of activator. In CD patients with severe disease necessitating surgical intervention, preoperative circulating RNASET2 protein levels were decreased compared to non-IBD subjects and rebounded post-operatively following removal of the inflamed region, with levels associated with allelic carriage. Furthermore, overexpression or treatment with recombinant RNASET2 significantly reduced IFN-γ secretion. These findings reveal that RNASET2 cis- and trans-acting variation contributed regulatory complexity and determined expression and provide a basis for linking genetic variation with CD pathobiology. These data may ultimately identify RNASET2 as an effective therapeutic target in a subset of CD patients with severe disease. |
format | Online Article Text |
id | pubmed-9709281 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97092812022-12-01 Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion Biener-Ramanujan, Eva Rosier, Florian Coetzee, Simon G. McGovern, Dermot D. P. Hazelett, Dennis Targan, Stephan R. Gonsky, Rivkah Front Immunol Immunology Ribonuclease T2 gene (RNASET2) variants are associated in genome wide association studies (GWAS) with risk for several autoimmune diseases, including Crohn’s disease (CD). In T cells, a functional and biological relationship exists between TNFSF15-mediated enhancement of IFN−γ production, mucosal inflammation and RNASET2. Disease risk variants are associated with decreased mRNA expression and clinical characteristics of severe CD; however, functional classifications of variants and underlying molecular mechanisms contributing to pathogenesis remain largely unknown. In this study we demonstrate that allelic imbalance of RNASET2 disease risk variant rs2149092 is associated with transcriptional and post-transcriptional mechanisms regulating transcription factor binding, promoter-transactivation and allele-specific expression. RNASET2 mRNA expression decreases in response to multiple modes of T cell activation and recovers following elimination of activator. In CD patients with severe disease necessitating surgical intervention, preoperative circulating RNASET2 protein levels were decreased compared to non-IBD subjects and rebounded post-operatively following removal of the inflamed region, with levels associated with allelic carriage. Furthermore, overexpression or treatment with recombinant RNASET2 significantly reduced IFN-γ secretion. These findings reveal that RNASET2 cis- and trans-acting variation contributed regulatory complexity and determined expression and provide a basis for linking genetic variation with CD pathobiology. These data may ultimately identify RNASET2 as an effective therapeutic target in a subset of CD patients with severe disease. Frontiers Media S.A. 2022-11-16 /pmc/articles/PMC9709281/ /pubmed/36466822 http://dx.doi.org/10.3389/fimmu.2022.999155 Text en Copyright © 2022 Biener-Ramanujan, Rosier, Coetzee, McGovern, Hazelett, Targan and Gonsky https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Biener-Ramanujan, Eva Rosier, Florian Coetzee, Simon G. McGovern, Dermot D. P. Hazelett, Dennis Targan, Stephan R. Gonsky, Rivkah Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title | Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title_full | Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title_fullStr | Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title_full_unstemmed | Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title_short | Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion |
title_sort | diagnostic and therapeutic potential of rnaset2 in crohn’s disease: disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-rnaset2 attenuates pro-inflammatory cytokine secretion |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9709281/ https://www.ncbi.nlm.nih.gov/pubmed/36466822 http://dx.doi.org/10.3389/fimmu.2022.999155 |
work_keys_str_mv | AT bienerramanujaneva diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT rosierflorian diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT coetzeesimong diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT mcgoverndermotdp diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT hazelettdennis diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT targanstephanr diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion AT gonskyrivkah diagnosticandtherapeuticpotentialofrnaset2incrohnsdiseasediseaseriskpolymorphismmodulatesallelicimbalanceinexpressionandcirculatingproteinlevelsandrecombinantrnaset2attenuatesproinflammatorycytokinesecretion |