Reversible promoter methylation determines fluctuating expression of acute phase proteins

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Abstract

Acute phase reactants (APRs) are secretory proteins exhibiting large expression changes in response to proinflammatory cytokines. Here we show that the expression pattern of a major APR, i.e. human C-reactive protein (CRP), is casually determined by DNMT3A and TET2-tuned promoter methylation status. CRP features a CpG-poor promoter with its CpG motifs located in binding sites of STAT3, C/EBP-β and NF-κB. These motifs are highly methylated at the resting state, but undergo STAT3- and NF-κB-dependent demethylation upon cytokine stimulation, leading to markedly enhanced recruitment of C/EBP-β that boosts CRP expression. Withdrawal of cytokines, by contrast, results in a rapid recovery of promoter methylation and termination of CRP induction. Further analysis suggests that reversible methylation also regulates the expression of highly inducible genes carrying CpG-poor promoters with APRs as representatives. Therefore, these CpG-poor promoters may evolve CpG-containing TF binding sites to harness dynamic methylation for prompt and reversible responses.

Data availability

Sequencing data have been deposited in GEO under accession code GSE146797

The following previously published data sets were used

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Article and author information

Author details

Shi-Chao Zhang

School of Life Sciences, Lanzhou University, Lanzhou, China

Competing interests
The authors declare that no competing interests exist.
Ming-Yu Wang

School of Life Sciences, Lanzhou University, Lanzhou, China

Competing interests
The authors declare that no competing interests exist.
Jun-Rui Feng

School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China

Competing interests
The authors declare that no competing interests exist.
Yue Chang

School of Life Sciences, Lanzhou University, Lanzhou, China

Competing interests
The authors declare that no competing interests exist.
Shang-Rong Ji

School of Life Sciences, Lanzhou University, Lanzhou, China

For correspondence
jsr@lzu.edu.cn

Competing interests
The authors declare that no competing interests exist.
Yi Wu

School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, China

For correspondence
wuy@lzu.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-0365-5590

Funding

National Natural Science Foundation of China (31671339,31870767)

Yi Wu

National Natural Science Foundation of China (31570749,31770819)

Shang-Rong Ji

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: The experiments conformed to the Guide for the Care and Use of Laboratory Animals published by NIH, and were conducted according to the protocols approved by the Ethics Committee of Animal Experiments of Xi'an Jiaotong University and Lanzhou University.

Copyright

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.