Principles Governing DNA Methylation during Neuronal Lineage and Subtype Specification
Principles Governing DNA Methylation during Neuronal Lineage and Subtype Specification
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DOI：
10.1523/jneurosci.4037-15.2016
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发表时间：
2016-02
期刊：
影响因子：
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通讯作者：
Ali Sharma;S. Klein;Luendreo P. Barboza;Niraj Lohdi;M. Toth
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作者：
Ali Sharma;S. Klein;Luendreo P. Barboza;Niraj Lohdi;M. Toth
虽然在早期神经元发育过程中进行了全面描述，但DNA甲基化/去甲基化在神经元谱系和亚型特化中的作用尚未得到很好的理解。通过研究小鼠海马和纹状体中两种不同的神经元祖细胞分化为主要神经元，我们揭示了大脑发育过程中神经元DNA甲基化的几个原则。(1)该程序包括三个阶段：在祖细胞增殖过程中的初始全基因组甲基化，随后是区域祖细胞向“年轻”海马/纹状体神经元过渡期间的甲基化丧失，然后在成熟为亚型特异性神经元期间通过甲基化获得逆转。(2)在前两个阶段，甲基化的获得和丧失仅限于CpG，而在第三个成熟阶段，甲基化也发生在两个谱系的非CpG位点。(3)甲基化/去甲基化，类似于转录，最初在两个谱系中高度相似，而成熟过程中甲基化和转录的多样化产生亚型特异性甲基化差异。(4)最初，甲基化靶向所有基因组位置，而后来，在早期和晚期分化期间，优选的靶标是具有增强子样活性的内含子/基因间序列。(5)差异甲基化的基因在连续的神经发育功能（如祖细胞增殖，迁移，轴突发生和突触传递）中富集;上调的基因代表当前和连续的阶段特异性功能，下调的基因代表不再需要的先前功能。我们的工作的主要结论是，神经元甲基化/去甲基化程序主要是发展与最小的谱系特异性，除了在最后阶段的发展，当神经元亚型特异性差异也出现。意义声明我们的工作是第一个描述一组相对简单的规则来控制体内神经元发育中的DNA甲基化和去甲基化。通过将神经发育分为三个主要阶段并对每个阶段应用规则，我们创建了一个矩阵，该矩阵全面描述了两个神经元谱系中的DNA甲基化/去甲基化事件，共有10种细胞类型跨越整个神经发育。除了增加我们对正常发育的表观遗传调控的理解，我们的工作将有助于破译环境扰动，如妊娠毒素，药物，压力，感染和后代忽视/虐待，干扰发育甲基化程序。
Although comprehensively described during early neuronal development, the role of DNA methylation/demethylation in neuronal lineage and subtype specification is not well understood. By studying two distinct neuronal progenitors as they differentiate to principal neurons in mouse hippocampus and striatum, we uncovered several principles governing neuronal DNA methylation during brain development. (1) The program consists of three stages: an initial genome-wide methylation during progenitor proliferation is followed by loss of methylation during the transition of regional progenitors to “young” hippocampal/striatal neurons, which is then reversed by gain in methylation during maturation to subtype-specific neurons. (2) At the first two stages, gain and loss of methylation are limited to CpGs, whereas during the third maturation stage, methylation also occurs at non-CpG sites in both lineages. (3) Methylation/demethylation, similar to transcription, are initially highly similar in the two lineages, whereas diversification in methylation and transcription during maturation creates subtype-specific methylation differences. (4) Initially, methylation targets all genomic locations, whereas later, during early and late differentiation, the preferred targets are intronic/intergenic sequences with enhancer-like activity. (5) Differentially methylated genes are enriched in sequential neurodevelopmental functions (such as progenitor proliferation, migration, neuritogenesis, and synaptic transmission); upregulated genes represent current and consecutive stage-specific functions, and downregulated genes represent preceding functions that are no longer required. The main conclusion of our work is that the neuronal methylation/demethylation program is predominantly developmental with minimal lineage specificity, except in the final stage of development when neuron subtype-specific differences also emerge. SIGNIFICANCE STATEMENT Our work is the first to describe a set of relatively simple rules that govern DNA methylation and demethylation in neuronal development in vivo. By dividing neurodevelopment to three major stages and applying rules to each of them, we created a matrix that comprehensively describes DNA methylation/demethylation events in two neuronal lineages, with a total of 10 cell types spanning the entire neurodevelopment. Beyond increasing our understanding of the epigenetic regulation of normal development, our work will be useful in deciphering how environmental perturbations, such as gestational toxins, drugs, stress, infection, and offspring neglect/maltreatment, interfere with the developmental methylation program.