Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes.
Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylatio...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2016-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5147832?pdf=render |
| _version_ | 1811305664361791488 |
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| author | Dan Su Xuting Wang Michelle R Campbell Devin K Porter Gary S Pittman Brian D Bennett Ma Wan Neal A Englert Christopher L Crowl Ryan N Gimple Kelly N Adamski Zhiqing Huang Susan K Murphy Douglas A Bell |
| author_facet | Dan Su Xuting Wang Michelle R Campbell Devin K Porter Gary S Pittman Brian D Bennett Ma Wan Neal A Englert Christopher L Crowl Ryan N Gimple Kelly N Adamski Zhiqing Huang Susan K Murphy Douglas A Bell |
| author_sort | Dan Su |
| collection | DOAJ |
| description | Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology. |
| first_indexed | 2024-04-13T08:30:34Z |
| format | Article |
| id | doaj.art-d17b6c86f5af4f618f0b414164b95c75 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-13T08:30:34Z |
| publishDate | 2016-01-01 |
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| spelling | doaj.art-d17b6c86f5af4f618f0b414164b95c752022-12-22T02:54:16ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-011112e016648610.1371/journal.pone.0166486Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes.Dan SuXuting WangMichelle R CampbellDevin K PorterGary S PittmanBrian D BennettMa WanNeal A EnglertChristopher L CrowlRyan N GimpleKelly N AdamskiZhiqing HuangSusan K MurphyDouglas A BellTobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking-associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.http://europepmc.org/articles/PMC5147832?pdf=render |
| spellingShingle | Dan Su Xuting Wang Michelle R Campbell Devin K Porter Gary S Pittman Brian D Bennett Ma Wan Neal A Englert Christopher L Crowl Ryan N Gimple Kelly N Adamski Zhiqing Huang Susan K Murphy Douglas A Bell Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. PLoS ONE |
| title | Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. |
| title_full | Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. |
| title_fullStr | Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. |
| title_full_unstemmed | Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. |
| title_short | Distinct Epigenetic Effects of Tobacco Smoking in Whole Blood and among Leukocyte Subtypes. |
| title_sort | distinct epigenetic effects of tobacco smoking in whole blood and among leukocyte subtypes |
| url | http://europepmc.org/articles/PMC5147832?pdf=render |
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