期刊
ELIFE
卷 9, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.61965
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资金
- Chinese Ministry of Science and Technology [2018YFE0203300]
- National Natural Science Foundation of China [31530047, 31761163001, 033/2017/AFJ]
- Chinese Academy of Sciences [XDB 39000000, QYZDY-SSW-SMC031]
- Youth Innovation Promotion Association of the Chinese Academy of Sciences [2017133, 2020097]
- Fundo para o Desenvolvimento das Ciencias e da Tecnologia [31761163001, 033/2017/AFJ]
Transcriptional memory allows certain genes to respond to previously experienced signals more robustly. However, whether and how the key proinflammatory cytokine TNF-alpha mediates transcriptional memory are poorly understood. Using HEK293F cells as a model system, we report that sustained TNF-alpha stimulation induces transcriptional memory dependent on TET enzymes. The hypomethylated status of transcriptional regulatory regions can be inherited, facilitating NF-kappa B binding and more robust subsequent activation. A high initial methylation level and CpG density around kappa B 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-alpha stimulation. Our study reveals that TNF-alpha-mediated transcriptional memory is governed by active DNA demethylation and greatly sensitizes memory genes to much lower doses of inflammatory cues.
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