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System-Wide Associations between DNA-Methylation, Gene Expression, and Humoral Immune Response to Influenza Vaccination.

Zimmermann MT, Oberg AL, Grill DE, Ovsyannikova IG, Haralambieva IH, Kennedy RB, Poland GA - PLoS ONE (2016)

Bottom Line: The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation.Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity.Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT
Failure to achieve a protected state after influenza vaccination is poorly understood but occurs commonly among aged populations experiencing greater immunosenescence. In order to better understand immune response in the elderly, we studied epigenetic and transcriptomic profiles and humoral immune response outcomes in 50-74 year old healthy participants. Associations between DNA methylation and gene expression reveal a system-wide regulation of immune-relevant functions, likely playing a role in regulating a participant's propensity to respond to vaccination. Our findings show that sites of methylation regulation associated with humoral response to vaccination impact known cellular differentiation signaling and antigen presentation pathways. We performed our analysis using per-site and regionally average methylation levels, in addition to continuous or dichotomized outcome measures. The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation. Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity. Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response. Additionally, CpGs that individually predict humoral immune responses are enriched for polycomb-group and FOXP2 transcription factor binding sites. The most robust associations implicate differential methylation affecting gene expression levels of genes with known roles in immunity (e.g. HLA-B and HLA-DQB2) and immunosenescence. We believe our data and analysis strategy highlight new and interesting epigenetic trends affecting humoral response to vaccination against influenza; one of the most common and impactful viral pathogens.

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Related in: MedlinePlus

Methylation-HAI network based on linear regression models.Day0 methylation levels of cis-acting CpGs and the change in HAI titer between Day28 and Day0 are used to generate linear regression models. Coloring and display is as in Fig 1.
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pone.0152034.g002: Methylation-HAI network based on linear regression models.Day0 methylation levels of cis-acting CpGs and the change in HAI titer between Day28 and Day0 are used to generate linear regression models. Coloring and display is as in Fig 1.

Mentions: We analyzed the association between baseline methylation and HAI at multiple timepoints using linear regression models, showing the top results in Table 2 and the full list in S7 Table. Cis-acting CpGs showed temporal patterns of biologic function enrichment with new and differentially activated biologic processes observed through Day 3 and Day 28 (Fig 2). Few genes (8.2%) are recapitulated at a second timepoint (S1 Fig). The strongest statistical associations are plotted in S5 Fig, and are for the HLA genes HLA-DQB2 (p = 9.57E-6; q = 0.38) and HLA-B (p = 1.08E-5; q = 0.38).


System-Wide Associations between DNA-Methylation, Gene Expression, and Humoral Immune Response to Influenza Vaccination.

Zimmermann MT, Oberg AL, Grill DE, Ovsyannikova IG, Haralambieva IH, Kennedy RB, Poland GA - PLoS ONE (2016)

Methylation-HAI network based on linear regression models.Day0 methylation levels of cis-acting CpGs and the change in HAI titer between Day28 and Day0 are used to generate linear regression models. Coloring and display is as in Fig 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816338&req=5

pone.0152034.g002: Methylation-HAI network based on linear regression models.Day0 methylation levels of cis-acting CpGs and the change in HAI titer between Day28 and Day0 are used to generate linear regression models. Coloring and display is as in Fig 1.
Mentions: We analyzed the association between baseline methylation and HAI at multiple timepoints using linear regression models, showing the top results in Table 2 and the full list in S7 Table. Cis-acting CpGs showed temporal patterns of biologic function enrichment with new and differentially activated biologic processes observed through Day 3 and Day 28 (Fig 2). Few genes (8.2%) are recapitulated at a second timepoint (S1 Fig). The strongest statistical associations are plotted in S5 Fig, and are for the HLA genes HLA-DQB2 (p = 9.57E-6; q = 0.38) and HLA-B (p = 1.08E-5; q = 0.38).

Bottom Line: The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation.Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity.Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, United States of America.

ABSTRACT
Failure to achieve a protected state after influenza vaccination is poorly understood but occurs commonly among aged populations experiencing greater immunosenescence. In order to better understand immune response in the elderly, we studied epigenetic and transcriptomic profiles and humoral immune response outcomes in 50-74 year old healthy participants. Associations between DNA methylation and gene expression reveal a system-wide regulation of immune-relevant functions, likely playing a role in regulating a participant's propensity to respond to vaccination. Our findings show that sites of methylation regulation associated with humoral response to vaccination impact known cellular differentiation signaling and antigen presentation pathways. We performed our analysis using per-site and regionally average methylation levels, in addition to continuous or dichotomized outcome measures. The genes and molecular functions implicated by each analysis were compared, highlighting different aspects of the biologic mechanisms of immune response affected by differential methylation. Both cis-acting (within the gene or promoter) and trans-acting (enhancers and transcription factor binding sites) sites show significant associations with measures of humoral immunity. Specifically, we identified a group of CpGs that, when coordinately hypo-methylated, are associated with lower humoral immune response, and methylated with higher response. Additionally, CpGs that individually predict humoral immune responses are enriched for polycomb-group and FOXP2 transcription factor binding sites. The most robust associations implicate differential methylation affecting gene expression levels of genes with known roles in immunity (e.g. HLA-B and HLA-DQB2) and immunosenescence. We believe our data and analysis strategy highlight new and interesting epigenetic trends affecting humoral response to vaccination against influenza; one of the most common and impactful viral pathogens.

Show MeSH
Related in: MedlinePlus