Reversible promoter methylation determines fluctuating expression of acute phase proteins
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
-
Bisulfite-Seq analysis of WGBS_Lib 11 derived from human liver cellsNCBI Gene Expression Omnibus, GSM916049.
-
liver_N3_BSNCBI Gene Expression Omnibus, GSM1716965.
-
Whole Genome Shotgun Bisulfite Sequencing of Fat Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120331.
-
Whole Genome Shotgun Bisulfite Sequencing of Adrenal Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120325.
-
Whole Genome Shotgun Bisulfite Sequencing of Aorta Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120329.
-
Whole Genome Shotgun Bisulfite Sequencing of Esophagus Cells from Human STL003NCBI Gene Expression Omnibus, GSM983649.
-
Whole Genome Shotgun Bisulfite Sequencing of Gastric Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120333.
-
Whole Genome Shotgun Bisulfite Sequencing of Lung Cells from Human STL002NCBI Gene Expression Omnibus, GSM983647.
-
Whole Genome Shotgun Bisulfite Sequencing of Ovary Cells from Human STL002NCBI Gene Expression Omnibus, GSM1120323.
-
Whole Genome Shotgun Bisulfite Sequencing of Psoas Cells from Human STL003NCBI Gene Expression Omnibus, GSM1010986.
-
Whole Genome Shotgun Bisulfite Sequencing of Right Atrium Cells from Human STL003NCBI Gene Expression Omnibus, GSM1120335.
-
Whole Genome Shotgun Bisulfite Sequencing of Sigmoid Colon Cells from Human STL001NCBI Gene Expression Omnibus, GSM983645.
-
Whole Genome Shotgun Bisulfite Sequencing of Spleen Cells from Human STL003NCBI Gene Expression Omnibus, GSM983652.
-
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.
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.
Metrics
-
- 1,585
- views
-
- 190
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Computational and Systems Biology
- Immunology and Inflammation
Diverse antibody repertoires spanning multiple lymphoid organs (i.e., bone marrow, spleen, lymph nodes) form the foundation of protective humoral immunity. Changes in their composition across lymphoid organs are a consequence of B-cell selection and migration events leading to a highly dynamic and unique physiological landscape of antibody repertoires upon antigenic challenge (e.g., vaccination). However, to what extent B cells encoding identical or similar antibody sequences (clones) are distributed across multiple lymphoid organs and how this is shaped by the strength of a humoral response remains largely unexplored. Here, we performed an in-depth systems analysis of antibody repertoires across multiple distinct lymphoid organs of immunized mice and discovered that organ-specific antibody repertoire features (i.e., germline V-gene usage and clonal expansion profiles) equilibrated upon a strong humoral response (multiple immunizations and high serum titers). This resulted in a surprisingly high degree of repertoire consolidation, characterized by highly connected and overlapping B-cell clones across multiple lymphoid organs. Finally, we revealed distinct physiological axes indicating clonal migrations and showed that antibody repertoire consolidation directly correlated with antigen specificity. Our study uncovered how a strong humoral response resulted in a more uniform but redundant physiological landscape of antibody repertoires, indicating that increases in antibody serum titers were a result of synergistic contributions from antigen-specific B-cell clones distributed across multiple lymphoid organs. Our findings provide valuable insights for the assessment and design of vaccine strategies.
-
- Immunology and Inflammation
Adipose tissue inflammation is now considered to be a key process underlying metabolic diseases in obese individuals. However, it remains unclear how adipose inflammation is initiated and maintained or the mechanism by which inflammation develops. We found that microRNA-802 (Mir802) expression in adipose tissue is progressively increased with the development of dietary obesity in obese mice and humans. The increasing trend of Mir802 preceded the accumulation of macrophages. Adipose tissue-specific knockout of Mir802 lowered macrophage infiltration and ameliorated systemic insulin resistance. Conversely, the specific overexpression of Mir802 in adipose tissue aggravated adipose inflammation in mice fed a high-fat diet. Mechanistically, Mir802 activates noncanonical and canonical NF-κB pathways by targeting its negative regulator, TRAF3. Next, NF-κB orchestrated the expression of chemokines and SREBP1, leading to strong recruitment and M1-like polarization of macrophages. Our findings indicate that Mir802 endows adipose tissue with the ability to recruit and polarize macrophages, which underscores Mir802 as an innovative and attractive candidate for miRNA-based immune therapy for adipose inflammation.