Xue Jing, Schoenrock Sarah A, Valdar William, Tarantino Lisa M, Ideraabdullah Folami Y
Nutrition Research Institute, University of North Carolina, Kannapolis, NC 28081 USA.
Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC 27599 USA ; Neurobiology Curriculum, University of North Carolina, Chapel Hill, NC 27599 USA.
Clin Epigenetics. 2016 Oct 12;8:107. doi: 10.1186/s13148-016-0276-4. eCollection 2016.
Environmental perturbation of epigenetic mechanisms is linked to a growing number of diseases. Characterizing the role environmental factors play in modifying the epigenome is important for disease etiology. Vitamin D is an essential nutrient affecting brain, bone, heart, immune and reproductive health. Vitamin D insufficiency is a global issue, and the role in maternal and child health remains under investigation.
We used Collaborative Cross (CC) inbred mice to characterize the effect of maternal vitamin D depletion on offspring phenotypic and epigenetic outcomes at imprinted domains (, , , and ) in the soma (liver) and germline (sperm). We assessed outcomes in two generations of offspring to determine heritability. We used reciprocal crosses between lines CC001/Unc and CC011/Unc to investigate parent of origin effects.
Maternal vitamin D deficiency led to altered body weight and DNA methylation in two generations of offspring. Loci assayed in adult liver and sperm were mostly hypomethylated, but changes were few and small in effect size (<7 % difference on average). There was no change in total expression of genes adjacent to methylation changes in neonatal liver. Methylation changes were cell type specific such that changes at were present in sperm but not in liver. Some methylation changes were distinct between generations such that methylation changes at the in second-generation liver were not present in first-generation sperm or liver. Interestingly, some diet-dependent changes in body weight and methylation were seemingly influenced by parent of origin such that reciprocal crosses exhibited inverse effects.
These findings demonstrate that maternal vitamin D status plays a role in determining DNA methylation state in the germline and soma. Detection of methylation changes in the unexposed second-generation demonstrates that maternal vitamin D depletion can have long-term effects on the epigenome of subsequent generations. Differences in vitamin D-dependent epigenetic state between cell types and generations indicate perturbation of the epigenetic landscape rather than a targeted, locus-specific effect. While the biological importance of these subtle changes remains unclear, they warrant an investigation of epigenome-wide effects of maternal vitamin D depletion.
表观遗传机制的环境扰动与越来越多的疾病相关。确定环境因素在修饰表观基因组中所起的作用对于疾病病因学研究至关重要。维生素D是一种影响大脑、骨骼、心脏、免疫和生殖健康的必需营养素。维生素D不足是一个全球性问题，其在母婴健康方面的作用仍在研究中。
我们使用协作杂交（CC）近交系小鼠来确定母体维生素D缺乏对后代体细胞（肝脏）和生殖系（精子）中印迹区域（、、、和）的表型和表观遗传结果的影响。我们评估了两代后代的结果以确定遗传力。我们使用CC001/Unc和CC011/Unc品系之间的正反交来研究亲本来源效应。
母体维生素D缺乏导致两代后代体重和DNA甲基化发生改变。在成年肝脏和精子中检测的位点大多发生低甲基化，但变化数量少且效应大小小（平均差异<7%）。新生儿肝脏中与甲基化变化相邻的基因总表达没有变化。甲基化变化具有细胞类型特异性，例如在精子中存在，但在肝脏中不存在。两代之间的一些甲基化变化不同，例如第二代肝脏中的甲基化变化在第一代精子或肝脏中不存在。有趣的是，一些体重和甲基化的饮食依赖性变化似乎受亲本来源影响，使得正反交表现出相反的效应。
这些发现表明母体维生素D状态在决定生殖系和体细胞中的DNA甲基化状态方面发挥作用。在未暴露的第二代中检测到甲基化变化表明母体维生素D缺乏可对后代的表观基因组产生长期影响。细胞类型和代际之间维生素D依赖性表观遗传状态的差异表明表观遗传格局受到扰动，而不是靶向的、位点特异性效应。虽然这些细微变化的生物学重要性尚不清楚，但它们值得对母体维生素D缺乏的全表观基因组效应进行研究。
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