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Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation
Resistin is a key cytokine associated with metabolic and inflammatory diseases. Especially in East Asian populations, the expression levels are strongly influenced by genetic polymorphisms. Mechanisms and functional implications of this genetic control are still unknown. By employing reporter assays...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811637/ https://www.ncbi.nlm.nih.gov/pubmed/31645609 http://dx.doi.org/10.1038/s41598-019-51592-0 |
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author | Kumar, Dilip Lee, Bernett Puan, Kia Joo Lee, Wendy Luis, Boris San Yusof, Nurhashikin Andiappan, Anand Kumar Del Rosario, Ricardo Poschmann, Jeremie Kumar, Pavanish DeLibero, Gennaro Singhal, Amit Prabhakar, Shyam De Yun, Wang Poidinger, Michael Rötzschke, Olaf |
author_facet | Kumar, Dilip Lee, Bernett Puan, Kia Joo Lee, Wendy Luis, Boris San Yusof, Nurhashikin Andiappan, Anand Kumar Del Rosario, Ricardo Poschmann, Jeremie Kumar, Pavanish DeLibero, Gennaro Singhal, Amit Prabhakar, Shyam De Yun, Wang Poidinger, Michael Rötzschke, Olaf |
author_sort | Kumar, Dilip |
collection | PubMed |
description | Resistin is a key cytokine associated with metabolic and inflammatory diseases. Especially in East Asian populations, the expression levels are strongly influenced by genetic polymorphisms. Mechanisms and functional implications of this genetic control are still unknown. By employing reporter assays, EMSA, inhibition studies, bisulphite sequencing, ChIP-Seq and gene-editing we show that the p50/p50 homodimer known to act as repressor for a number of pro-inflammatory genes plays a central role in the genetic regulation of resistin in monocytes along with promoter methylation. In the common RETN haplotype p50/p50 constitutively dampens the expression by binding to the promoter. In an Asian haplotype variant however this interaction is disrupted by the A allele of rs3219175. The SNP is in very close linkage to rs34861192, a CpG SNP, located 280 bp upstream which provides an allele-specific C-methylation site. rs34861192 is located in a 100 bp region found to be methylated in the common but not in the Asian haplotype, resulting in the latter having a higher basal expression, which also associates with elevated histone acetylation (H3K27ac). Genotype associations within cohort data of 200 East Asian individuals revealed significant associations between this haplotype and the plasma levels of factors such as TGF-b, S100B, sRAGE and IL-8 as well as with myeloid DC counts. Thus, the common RETN haplotype is tightly regulated by the epigenetic mechanism linked to p50/p50-binding. This control is lost in the Asian haplotype, which may have evolved to balance the antagonistic RETN effects on pathogen protection vs. metabolic and inflammatory disease induction. |
format | Online Article Text |
id | pubmed-6811637 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68116372019-10-25 Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation Kumar, Dilip Lee, Bernett Puan, Kia Joo Lee, Wendy Luis, Boris San Yusof, Nurhashikin Andiappan, Anand Kumar Del Rosario, Ricardo Poschmann, Jeremie Kumar, Pavanish DeLibero, Gennaro Singhal, Amit Prabhakar, Shyam De Yun, Wang Poidinger, Michael Rötzschke, Olaf Sci Rep Article Resistin is a key cytokine associated with metabolic and inflammatory diseases. Especially in East Asian populations, the expression levels are strongly influenced by genetic polymorphisms. Mechanisms and functional implications of this genetic control are still unknown. By employing reporter assays, EMSA, inhibition studies, bisulphite sequencing, ChIP-Seq and gene-editing we show that the p50/p50 homodimer known to act as repressor for a number of pro-inflammatory genes plays a central role in the genetic regulation of resistin in monocytes along with promoter methylation. In the common RETN haplotype p50/p50 constitutively dampens the expression by binding to the promoter. In an Asian haplotype variant however this interaction is disrupted by the A allele of rs3219175. The SNP is in very close linkage to rs34861192, a CpG SNP, located 280 bp upstream which provides an allele-specific C-methylation site. rs34861192 is located in a 100 bp region found to be methylated in the common but not in the Asian haplotype, resulting in the latter having a higher basal expression, which also associates with elevated histone acetylation (H3K27ac). Genotype associations within cohort data of 200 East Asian individuals revealed significant associations between this haplotype and the plasma levels of factors such as TGF-b, S100B, sRAGE and IL-8 as well as with myeloid DC counts. Thus, the common RETN haplotype is tightly regulated by the epigenetic mechanism linked to p50/p50-binding. This control is lost in the Asian haplotype, which may have evolved to balance the antagonistic RETN effects on pathogen protection vs. metabolic and inflammatory disease induction. Nature Publishing Group UK 2019-10-23 /pmc/articles/PMC6811637/ /pubmed/31645609 http://dx.doi.org/10.1038/s41598-019-51592-0 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Kumar, Dilip Lee, Bernett Puan, Kia Joo Lee, Wendy Luis, Boris San Yusof, Nurhashikin Andiappan, Anand Kumar Del Rosario, Ricardo Poschmann, Jeremie Kumar, Pavanish DeLibero, Gennaro Singhal, Amit Prabhakar, Shyam De Yun, Wang Poidinger, Michael Rötzschke, Olaf Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title | Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title_full | Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title_fullStr | Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title_full_unstemmed | Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title_short | Resistin expression in human monocytes is controlled by two linked promoter SNPs mediating NFKB p50/p50 binding and C-methylation |
title_sort | resistin expression in human monocytes is controlled by two linked promoter snps mediating nfkb p50/p50 binding and c-methylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811637/ https://www.ncbi.nlm.nih.gov/pubmed/31645609 http://dx.doi.org/10.1038/s41598-019-51592-0 |
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