Sustained TNF-α stimulation induces transcriptional memory that greatly enhances signal sensitivity and robustness
- Chinese Academy of Sciences, China
- University of Macau, China
Abstract
Transcriptional memory allows certain genes to respond to previously experienced signals more robustly. However, whether and how the key proinflammatory cytokine TNF-α mediates transcriptional memory are poorly understood. Using HEK293F cells as a model system, we report that sustained TNF-α stimulation induces transcriptional memory dependent on TET enzymes. The hypomethylated status of transcriptional regulatory regions can be inherited, facilitating NF-κB binding and more robust subsequent activation. A high initial methylation level and CpG density around κB sites are correlated with the functional potential of transcriptional memory modules. Interestingly, the CALCB gene, encoding the proven migraine therapeutic target CGRP, exhibits the best transcriptional memory. A neighboring primate-specific endogenous retrovirus stimulates more rapid, more strong and at least 100-fold more sensitive CALCB induction in subsequent TNF-α stimulation. Our study reveals that TNF-α-mediated transcriptional memory is governed by active DNA demethylation and greatly sensitizes memory genes to much lower doses of inflammatory cues.
Data availability
All high-throughput data generated in this study have been deposited in NCBI GEO database under accession number GSE152146, except that p65 ChIP-seq data for 0 h and 12 h TNF-α treatments have been deposited under the accession number GSE121361 (Zhao et al., 2019).
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TNF induced inflammatory transcription dynamics and epigenetic changesNCBI Gene Expression Omnibus, GSE152146.
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TNF-α induces IL-32 expression in HEK293 cellsNCBI Gene Expression Omnibus, GSE121361.
Article and author information
Author details
Funding
the Chinese ministry of Science and technology (2018YFE0203300)
- Bing Zhu
the national natural science foundation of China (31530047)
- Bing Zhu
the national natural science foundation of China (31761163001)
- Bing Zhu
Chinese Academy of Sciences (XDB 39000000)
- Bing Zhu
Chinese Academy of Sciences (QYZDY-SSW-SMC031)
- Bing Zhu
Youth Innovation Promotion Association of the Chinese Academy of Sciences (2017133)
- Zhuqiang Zhang
Youth Innovation Promotion Association of the Chinese Academy of Sciences (2020097)
- Jun Xiong
the NSFC-FDCT joint grant (31761163001)
- Bing Zhu
the NSFC-FDCT joint grant (033/2017/AFJ)
- Gang Li
This work was supported by the Chinese Ministry of Science and Technology (2018YFE0203300), the NSFC-FDCT joint grant (31761163001 for B.Z and 033/2017/AFJ for G.L.), the National Natural Science Foundation of China (31530047, 31761163001), and the Chinese Academy of Sciences (XDB 39000000 and QYZDY-SSW-SMC031). Z. Zhang and J.X. are supported by the Youth Innovation Promotion Association (2017133 and 2020097, respectively) of the Chinese Academy of Sciences.
Reviewing Editor
- Xiaobing Shi, Van Andel Institute, United States
Publication history
- Received: August 10, 2020
- Accepted: November 5, 2020
- Accepted Manuscript published: November 6, 2020 (version 1)
- Version of Record published: November 30, 2020 (version 2)
Copyright
© 2020, Zhao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Sustained TNF-α stimulation induces transcriptional memory that greatly enhances signal sensitivity and robustness
eLife 9:e61965.
https://doi.org/10.7554/eLife.61965
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