Dataset Information

Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

ABSTRACT: Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1?, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence.We compared the methylation profiles of the entire genomic loci encompassing the IL-1?, IL-6, IL-4, IL-10 and IL-8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group) from childhood to adolescence. We used the method of methylated DNA immunoprecipitation with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We found differentially methylated regions to associate with CPA in both the cytokine loci as well as in their transcription factors loci analyzed. Some of these differentially methylated regions were located in known regulatory regions whereas others, to our knowledge, were previously unknown as regulatory areas. However, using the ENCODE database, we were able to identify key regulatory elements in many of these regions that indicate that they might be involved in the regulation of cytokine expression.We provide here the first evidence for an association between differential DNA methylation in cytokines and their regulators in T cells and monocytes and male physical aggression.

SUBMITTER: Provencal N

PROVIDER: S-EPMC3747262 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

Provençal Nadine N Suderman Matthew J MJ Caramaschi Doretta D Wang Dongsha D Hallett Michael M Vitaro Frank F Tremblay Richard E RE Szyf Moshe M

PloS one 20130819 8

<h4>Background</h4>Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1α, IL-4, IL-6, IL-8 and IL-10, later in early adulthood. This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects ...[more]

PMID: 23977113

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Project description:Animal and human studies suggest that inflammation is associated with behavioral disorders including aggression. We have recently shown that physical aggression of boys during childhood is strongly associated with reduced plasma levels of cytokines IL-1a, IL-4, IL-6, IL-8 and IL-10, later in early adulthood (Provencal et al., unpublished data). This study tests the hypothesis that there is an association between differential DNA methylation regions in cytokine genes in T cells and monocytes DNA in adult subjects and a trajectory of physical aggression from childhood to adolescence. We compared the methylation profiles of the entire genomic loci encompassing the IL-1a, IL-6, IL-4, IL10 and IL8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6 genes in adult males on a chronic physical aggression trajectory (CPA) and males with the same background who followed a normal physical aggression trajectory (control group). We used the method of methylated DNA immunoprecipitation (MeDIP) with comprehensive cytokine gene loci and TF loci microarray hybridization, statistical analysis and false discovery rate correction. We recruited two groups of Caucasian males who were born in families with a low socioeconomic status and were living at the time of the present study within 200km from our laboratory. The first group, composed of 8 subjects, had a history of chronic physical aggression from age 6 to 15 years (chronic physical aggression group, CPA). The second group, composed of 12 subjects, was recruited from the same longitudinal studies but included only those who did not have a history of chronic physical aggression from age 6 to 15 (Control group, CG). Using custom-designed microarrays with 44K probes tiling cytokines IL-1a, IL-6, IL-4, IL10 and IL8 and three of their regulatory transcription factors (TF) NFkB1, NFAT5 and STAT6, we obtained DNA methylation profiles by meDIP-chip. Each profile was generated in triplicate.

Project description:BackgroundCytosine methylation is widespread in most eukaryotic genomes and is known to play a substantial role in various regulatory pathways. Unmethylated cytosines may be converted to uracil through the addition of sodium bisulphite, allowing genome-wide quantification of cytosine methylation via high-throughput sequencing. The data thus acquired allows the discovery of methylation 'loci'; contiguous regions of methylation consistently methylated across biological replicates. The mapping of these loci allows for associations with other genomic factors to be identified, and for analyses of differential methylation to take place.ResultsThe segmentSeq R package is extended to identify methylation loci from high-throughput sequencing data from multiple experimental conditions. A statistical model is then developed that accounts for biological replication and variable rates of non-conversion of cytosines in each sample to compute posterior likelihoods of methylation at each locus within an empirical Bayesian framework. The same model is used as a basis for analysis of differential methylation between multiple experimental conditions with the baySeq R package. We demonstrate the capability of this method to analyse complex data sets in an analysis of data derived from multiple Dicer-like mutants in Arabidopsis. This reveals several novel behaviours at distinct sets of loci in response to loss of one or more of the Dicer-like proteins that indicate an antagonistic relationship between the Dicer-like proteins at at least some methylation loci. Finally, we show in simulation studies that this approach can be significantly more powerful in the detection of differential methylation than many existing methods in data derived from both mammalian and plant systems.ConclusionsThe methods developed here make it possible to analyse high-throughput sequencing of the methylome of any given organism under a diverse set of experimental conditions. The methods are able to identify methylation loci and evaluate the likelihood that a region is truly methylated under any given experimental condition, allowing for downstream analyses that characterise differences between methylated and non-methylated regions of the genome. Futhermore, diverse patterns of differential methylation may also be characterised from these data.

Dataset Information

Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

Publications

Differential DNA methylation regions in cytokine and transcription factor genomic loci associate with childhood physical aggression.

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