Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada ; Research Unit on Children's Psycho-Social Maladjustment and Ste-Justine Hospital Research Center, University of Montreal, Montreal, Quebec, Canada ; Sackler Program for Epigenetics and Psychobiology, McGill University, Montreal, Quebec, Canada.
PLoS One. 2013 Aug 19;8(8):e71691. doi: 10.1371/journal.pone.0071691. eCollection 2013.
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 and a trajectory of physical aggression from childhood to adolescence.
METHODOLOGY/PRINCIPAL FINDINGS: We compared the methylation profiles of the entire genomic loci encompassing the IL-1α, 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.
动物和人类研究表明，炎症与包括攻击性在内的行为障碍有关。我们最近表明，儿童时期男孩的身体攻击性与成年早期血浆中细胞因子 IL-1α、IL-4、IL-6、IL-8 和 IL-10 的水平降低密切相关。本研究检验了以下假设：在 T 细胞和单核细胞 DNA 中的细胞因子基因的差异 DNA 甲基化区域与成年受试者的身体攻击性轨迹（从儿童期到青春期）之间存在关联。
方法/主要发现：我们比较了在慢性身体攻击性轨迹（CPA）的成年男性和具有相同背景的在儿童期到青春期遵循正常身体攻击性轨迹（对照组）的男性的整个基因组座涵盖 IL-1α、IL-6、IL-4、IL-10 和 IL-8 以及三个调节转录因子（TF）NFkB1、NFAT5 和 STAT6 基因的 DNA 甲基化谱。我们使用了甲基化 DNA 免疫沉淀与综合细胞因子基因座和 TF 基因座微阵列杂交、统计分析和错误发现率校正的方法。我们发现，在细胞因子基因座和其转录因子基因座分析中，与 CPA 相关的差异甲基化区域。这些差异甲基化区域中的一些位于已知的调节区域，而其他区域，据我们所知，以前未知为调节区域。然而，使用 ENCODE 数据库，我们能够识别出这些区域中的许多关键调节元件，表明它们可能参与细胞因子表达的调节。
我们在这里首次提供了证据，证明 T 细胞和单核细胞中的细胞因子及其调节剂的差异 DNA 甲基化与男性身体攻击性之间存在关联。
