RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor
Abstract Persistent microglial activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylase JMJD3 inhibitor, GSK-J4, was prov...
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doaj-f6fc55853b0b4d63a8c8340c456ed9532020-12-08T01:12:08ZengNature Publishing GroupScientific Reports2045-23222017-07-017111910.1038/s41598-017-06914-5RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitorAmitabh Das0Sarder Arifuzzaman1Taeho Yoon2Sun Hwa Kim3Jin Choul Chai4Young Seek Lee5Kyoung Hwa Jung6Young Gyu Chai7Institute of Natural Science & Technology, Hanyang UniversityDepartment of Bionanotechnology, Hanyang UniversityDepartment of Molecular & Life Sciences, Hanyang UniversityDepartment of Molecular & Life Sciences, Hanyang UniversityDepartment of Molecular & Life Sciences, Hanyang UniversityDepartment of Molecular & Life Sciences, Hanyang UniversityInstitute of Natural Science & Technology, Hanyang UniversityDepartment of Bionanotechnology, Hanyang UniversityAbstract Persistent microglial activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylase JMJD3 inhibitor, GSK-J4, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for GSK-J4 molecular targets has not been undertaken in microglia. To study the immuno-modulatory effects of GSK-J4 at the transcriptomic level, triplicate RNA sequencing and quantitative real-time PCR analyses were performed with resting, GSK-J4-, LPS- and LPS + GSK-J4-challenged primary microglial (PM) and BV-2 microglial cells. Among the annotated genes, the transcriptional sequencing of microglia that were treated with GSK-J4 revealed a selective effect on LPS-induced gene expression, in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent transcription factors TFs, as well as previously unidentified genes that are important in inflammation was suppressed. Furthermore, we showed that GSK-J4 controls are important inflammatory gene targets by modulating STAT1, IRF7, and H3K27me3 levels at their promoter sites. These unprecedented results demonstrate that the histone demethylase inhibitor GSK-J4 could have therapeutic applications for neuroinflammatory diseases.https://doi.org/10.1038/s41598-017-06914-5 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Amitabh Das Sarder Arifuzzaman Taeho Yoon Sun Hwa Kim Jin Choul Chai Young Seek Lee Kyoung Hwa Jung Young Gyu Chai |
spellingShingle |
Amitabh Das Sarder Arifuzzaman Taeho Yoon Sun Hwa Kim Jin Choul Chai Young Seek Lee Kyoung Hwa Jung Young Gyu Chai RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor Scientific Reports |
author_facet |
Amitabh Das Sarder Arifuzzaman Taeho Yoon Sun Hwa Kim Jin Choul Chai Young Seek Lee Kyoung Hwa Jung Young Gyu Chai |
author_sort |
Amitabh Das |
title |
RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor |
title_short |
RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor |
title_full |
RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor |
title_fullStr |
RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor |
title_full_unstemmed |
RNA sequencing reveals resistance of TLR4 ligand-activated microglial cells to inflammation mediated by the selective jumonji H3K27 demethylase inhibitor |
title_sort |
rna sequencing reveals resistance of tlr4 ligand-activated microglial cells to inflammation mediated by the selective jumonji h3k27 demethylase inhibitor |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-07-01 |
description |
Abstract Persistent microglial activation is associated with the production and secretion of various pro-inflammatory genes, cytokines and chemokines, which may initiate or amplify neurodegenerative diseases. A novel synthetic histone 3 lysine 27 (H3K27) demethylase JMJD3 inhibitor, GSK-J4, was proven to exert immunosuppressive activities in macrophages. However, a genome-wide search for GSK-J4 molecular targets has not been undertaken in microglia. To study the immuno-modulatory effects of GSK-J4 at the transcriptomic level, triplicate RNA sequencing and quantitative real-time PCR analyses were performed with resting, GSK-J4-, LPS- and LPS + GSK-J4-challenged primary microglial (PM) and BV-2 microglial cells. Among the annotated genes, the transcriptional sequencing of microglia that were treated with GSK-J4 revealed a selective effect on LPS-induced gene expression, in which the induction of cytokines/chemokines, interferon-stimulated genes, and prominent transcription factors TFs, as well as previously unidentified genes that are important in inflammation was suppressed. Furthermore, we showed that GSK-J4 controls are important inflammatory gene targets by modulating STAT1, IRF7, and H3K27me3 levels at their promoter sites. These unprecedented results demonstrate that the histone demethylase inhibitor GSK-J4 could have therapeutic applications for neuroinflammatory diseases. |
url |
https://doi.org/10.1038/s41598-017-06914-5 |
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