Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells
The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper...
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2021-02-01
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doaj-21a0e4eb908142b088a2edcc122efa892021-02-18T08:46:25ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-02-011210.3389/fimmu.2021.630389630389Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T CellsZsuzsanna Ortutay0Anna Grönholm1Melina Laitinen2Melinda Keresztes-Andrei3Ismail Hermelo4Marko Pesu5Marko Pesu6Immunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandImmunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandImmunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandFaculty of Information Technology and Bionics, Pázmány Péter Catholic University, Budapest, HungaryComputational Biology, Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandImmunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, FinlandFimlab Laboratories, Tampere, FinlandThe proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific Furin gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of Furin gene was identified. When this region was deleted with CRISPR/Cas9 the production of Furin mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel Furin regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally, Furin genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of Furin expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.https://www.frontiersin.org/articles/10.3389/fimmu.2021.630389/fullFurin regulationsuper-enhancerinterferon gammap300proprotein convertase |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zsuzsanna Ortutay Anna Grönholm Melina Laitinen Melinda Keresztes-Andrei Ismail Hermelo Marko Pesu Marko Pesu |
spellingShingle |
Zsuzsanna Ortutay Anna Grönholm Melina Laitinen Melinda Keresztes-Andrei Ismail Hermelo Marko Pesu Marko Pesu Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells Frontiers in Immunology Furin regulation super-enhancer interferon gamma p300 proprotein convertase |
author_facet |
Zsuzsanna Ortutay Anna Grönholm Melina Laitinen Melinda Keresztes-Andrei Ismail Hermelo Marko Pesu Marko Pesu |
author_sort |
Zsuzsanna Ortutay |
title |
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells |
title_short |
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells |
title_full |
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells |
title_fullStr |
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells |
title_full_unstemmed |
Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells |
title_sort |
identification of novel genetic regulatory region for proprotein convertase furin and interferon gamma in t cells |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-02-01 |
description |
The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific Furin gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of Furin gene was identified. When this region was deleted with CRISPR/Cas9 the production of Furin mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel Furin regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally, Furin genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of Furin expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate. |
topic |
Furin regulation super-enhancer interferon gamma p300 proprotein convertase |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.630389/full |
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