Reversible promoter methylation determines fluctuating expression of acute phase proteins

• Published in: eLife 2020-03, Vol.9
• Main Authors: Zhang, Shi-Chao, Wang, Ming-Yu, Feng, Jun-Rui, Chang, Yue, Ji, Shang-Rong, Wu, Yi
• Format: Article
• Language: English
• Subjects: Acute phase proteins; Acute-Phase Proteins - genetics; Acute-Phase Proteins - metabolism; Analysis; Binding sites; C-reactive protein; C-Reactive Protein - genetics; CCAAT/enhancer-binding protein; Cell Line, Tumor; Cloning; CpG islands; CpG Islands - genetics; Cytokines; Cytokines - immunology; Demethylation; Deoxyribonucleic acid; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Esophagus; Gene Expression; Gene Expression Regulation; Genes; Humans; Immunology and Inflammation; Inflammation; Liver; Methylation; Methyltransferases; NF-κB protein; Plasma; Promoter Regions, Genetic; Promoters; Protein Processing, Post-Translational; Proteins; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Stat3 protein; Tumors; Wu Yi
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.51317

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 human APR, that is ( ), is casually determined by DNMT3A and TET2-tuned promoter methylation status. 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 expression. Withdrawal of cytokines, by contrast, results in a rapid recovery of promoter methylation and termination of 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.