Reversible promoter methylation determines fluctuating expression of acute phase proteins
- Lanzhou University, China
- Xi'an Jiaotong University, China
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
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Bisulfite-Seq analysis of WGBS_Lib 11 derived from human liver cellsNCBI Gene Expression Omnibus, GSM916049.
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liver_N3_BSNCBI Gene Expression Omnibus, GSM1716965.
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Whole Genome Shotgun Bisulfite Sequencing of Fat Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120331.
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Whole Genome Shotgun Bisulfite Sequencing of Adrenal Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120325.
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Whole Genome Shotgun Bisulfite Sequencing of Aorta Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120329.
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Whole Genome Shotgun Bisulfite Sequencing of Esophagus Cells from Human STL003NCBI Gene Expression Omnibus, GSM983649.
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Whole Genome Shotgun Bisulfite Sequencing of Gastric Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120333.
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Whole Genome Shotgun Bisulfite Sequencing of Lung Cells from Human STL002NCBI Gene Expression Omnibus, GSM983647.
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Whole Genome Shotgun Bisulfite Sequencing of Ovary Cells from Human STL002NCBI Gene Expression Omnibus, GSM1120323.
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Whole Genome Shotgun Bisulfite Sequencing of Psoas Cells from Human STL003NCBI Gene Expression Omnibus, GSM1010986.
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Whole Genome Shotgun Bisulfite Sequencing of Right Atrium Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120335.
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Whole Genome Shotgun Bisulfite Sequencing of Sigmoid Colon Cells from Human STL001NCBI Gene Expression Omnibus, GSM983645.
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Whole Genome Shotgun Bisulfite Sequencing of Spleen Cells from Human STL003NCBI Gene Expression Omnibus, GSM983652.
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Whole Genome Shotgun Bisulfite Sequencing of Thymus Cells from Human STL001NCBI Gene Expression Omnibus, GSM1120322.
Article and author information
Author details
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.
Reviewing Editor
- Deborah Bourc'his, Institut Curie, France
Publication history
- Received: August 25, 2019
- Accepted: March 27, 2020
- Accepted Manuscript published: March 30, 2020 (version 1)
- Version of Record published: April 6, 2020 (version 2)
Copyright
© 2020, Zhang 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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