Acevedo Nathalie, Reinius Lovisa E, Vitezic Morana, Fortino Vittorio, Söderhäll Cilla, Honkanen Hanna, Veijola Riitta, Simell Olli, Toppari Jorma, Ilonen Jorma, Knip Mikael, Scheynius Annika, Hyöty Heikki, Greco Dario, Kere Juha
Department of Medicine Solna, Translational Immunology Unit, Karolinska University Hospital, Stockholm, Sweden ; Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
Department of Biosciences and Nutrition, Center for Innovative Medicine, Karolinska Institutet, Stockholm, Sweden.
Clin Epigenetics. 2015 Mar 26;7(1):34. doi: 10.1186/s13148-015-0064-6. eCollection 2015.
Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip.
After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within -5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm.
This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
幼儿期血液白细胞中发生的与年龄相关的DNA甲基化变化可能反映表观遗传成熟。我们推测其中一些变化涉及白细胞生物学中至关重要的基因网络，并进行了一项前瞻性研究以阐明DNA甲基化的动态变化。在芬兰出生并参与1型糖尿病预测与预防研究的10名健康女孩出生后3、6、12、24、36、48和60个月时采集系列血样。使用HumanMethylation450 BeadChip测量DNA甲基化。
在筛选多态性和细胞谱系特异性特征后，794个CpG位点在所有儿童中显示出随年龄变化的显著DNA甲基化差异（41.6%随年龄甲基化，58.4%随年龄去甲基化，经Bonferroni校正的P值<0.01）。随年龄甲基化的CpG更频繁地位于基因体以及转录起始位点（TSS）的+5至+50千碱基（kb）范围内，并且在发育、神经元和质膜基因中富集。随年龄去甲基化的CpG与启动子和DNA酶I超敏位点相关，位于最接近TSS的-5至+5 kb范围内，并且在与免疫、抗原呈递、多梳蛋白组蛋白复合物和细胞质相关的基因中富集。
本研究表明，复杂炎症性疾病的易感基因座（例如，IRF5、NOD2和PTGER4）以及编码组蛋白修饰剂和染色质重塑因子的基因（例如，HDAC4、KDM2A、KDM2B、JARID2、ARID3A和SMARCD3）在幼儿期白细胞中会发生DNA甲基化变化。这些结果为理解白细胞成熟开辟了新的视角，并提供了一份CpG位点目录，在对儿童进行DNA甲基化研究时可能需要针对年龄效应进行校正。
