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.
- Yi Wu
- Shang-Rong Ji
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
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.
- Deborah Bourc'his, Institut Curie, France
© 2020, Zhang et al.
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