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Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription

Bmal1 (encoded by Arntl gene) is a core circadian clock gene that regulates various genes involved in circadian rhythm. Although Bmal1 is expressed rhythmically in macrophages, the role of Bmal1 in the regulation of their cellular function remains insufficiently understood. Here, we report that Bmal...

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Autores principales: Oishi, Yumiko, Hayashi, Shinichiro, Isagawa, Takayuki, Oshima, Motohiko, Iwama, Atsushi, Shimba, Shigeki, Okamura, Hitoshi, Manabe, Ichiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539165/
https://www.ncbi.nlm.nih.gov/pubmed/28765524
http://dx.doi.org/10.1038/s41598-017-07100-3
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author Oishi, Yumiko
Hayashi, Shinichiro
Isagawa, Takayuki
Oshima, Motohiko
Iwama, Atsushi
Shimba, Shigeki
Okamura, Hitoshi
Manabe, Ichiro
author_facet Oishi, Yumiko
Hayashi, Shinichiro
Isagawa, Takayuki
Oshima, Motohiko
Iwama, Atsushi
Shimba, Shigeki
Okamura, Hitoshi
Manabe, Ichiro
author_sort Oishi, Yumiko
collection PubMed
description Bmal1 (encoded by Arntl gene) is a core circadian clock gene that regulates various genes involved in circadian rhythm. Although Bmal1 is expressed rhythmically in macrophages, the role of Bmal1 in the regulation of their cellular function remains insufficiently understood. Here, we report that Bmal1 regulates time-dependent inflammatory responses following Toll-like receptor 4 (TLR4) activation by modulating enhancer activity. Global transcriptome analysis indicated that deletion of Arntl perturbed the time-dependent inflammatory responses elicited by TLR4 activation by Kdo2-lipid A (KLA). Although the recruitment of NF-κB p65 was unaffected, the acetylation status of lysine 27 of histone 3, which correlates positively with enhancer activity, was globally increased at PU.1-containing enhancers in Arntl (−/−) macrophages as compared to wild-type cells. Expression of Nr1d1 and Nr1d2, encoding RevErb transcription factors, which repress enhancer RNA expression, was significantly decreased in Arntl (−/−) macrophages. Moreover, the level of H3K27 acetylation was increased by Arntl deletion at RevErb-dependent eRNA-expressing enhancers. These results suggest that Bmal1 controls KLA-responsive enhancers, in part by regulating RevErb-directed eRNA transcription. Taken together, the results of this study show that the clock transcription factor network containing Bmal1 controls the inflammatory responses of macrophages by regulating the epigenetic states of enhancers.
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spelling pubmed-55391652017-08-07 Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription Oishi, Yumiko Hayashi, Shinichiro Isagawa, Takayuki Oshima, Motohiko Iwama, Atsushi Shimba, Shigeki Okamura, Hitoshi Manabe, Ichiro Sci Rep Article Bmal1 (encoded by Arntl gene) is a core circadian clock gene that regulates various genes involved in circadian rhythm. Although Bmal1 is expressed rhythmically in macrophages, the role of Bmal1 in the regulation of their cellular function remains insufficiently understood. Here, we report that Bmal1 regulates time-dependent inflammatory responses following Toll-like receptor 4 (TLR4) activation by modulating enhancer activity. Global transcriptome analysis indicated that deletion of Arntl perturbed the time-dependent inflammatory responses elicited by TLR4 activation by Kdo2-lipid A (KLA). Although the recruitment of NF-κB p65 was unaffected, the acetylation status of lysine 27 of histone 3, which correlates positively with enhancer activity, was globally increased at PU.1-containing enhancers in Arntl (−/−) macrophages as compared to wild-type cells. Expression of Nr1d1 and Nr1d2, encoding RevErb transcription factors, which repress enhancer RNA expression, was significantly decreased in Arntl (−/−) macrophages. Moreover, the level of H3K27 acetylation was increased by Arntl deletion at RevErb-dependent eRNA-expressing enhancers. These results suggest that Bmal1 controls KLA-responsive enhancers, in part by regulating RevErb-directed eRNA transcription. Taken together, the results of this study show that the clock transcription factor network containing Bmal1 controls the inflammatory responses of macrophages by regulating the epigenetic states of enhancers. Nature Publishing Group UK 2017-08-01 /pmc/articles/PMC5539165/ /pubmed/28765524 http://dx.doi.org/10.1038/s41598-017-07100-3 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Oishi, Yumiko
Hayashi, Shinichiro
Isagawa, Takayuki
Oshima, Motohiko
Iwama, Atsushi
Shimba, Shigeki
Okamura, Hitoshi
Manabe, Ichiro
Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title_full Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title_fullStr Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title_full_unstemmed Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title_short Bmal1 regulates inflammatory responses in macrophages by modulating enhancer RNA transcription
title_sort bmal1 regulates inflammatory responses in macrophages by modulating enhancer rna transcription
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5539165/
https://www.ncbi.nlm.nih.gov/pubmed/28765524
http://dx.doi.org/10.1038/s41598-017-07100-3
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