Functions and Mechanisms of Epigenetic Allelic Effects in the Brain

项目总结 由于不清楚的原因，神经精神障碍的表型是不同的，而且通常是同一基因。 与不同的疾病有关。我们对基因型和表型之间的联系的有限理解 阻碍了改进的诊断学和治疗学的发展。解决这一问题的NIMH战略优先事项 包括加深我们对调节因子的理解，这些调节因子改变基因表达并对 与精神疾病相关的大脑过程。对于等位基因特异的表观遗传效应，人们知之甚少 与杂合基因突变相互作用，影响表型变异和心理健康。的目标是 这项研究旨在揭示大脑中等位基因、蛋白质和细胞水平上的新的表观遗传效应。在一个 最近在《神经元》杂志上发表的文章中，我们发现了数千个差异表达母体和母体基因 小鼠和灵长类动物体内发育受调控的RNA水平的父系等位基因 大脑。我们将这些现象称为差异等位基因表达效应(DAEEs)。DAEE不是由于 大脑亚群中的遗传变异或基因组印记和涉及随机单等位基因表达 细胞。我们发现DAEEs与杂合突变相互作用，导致单等位基因脑细胞的嵌合体 在RNA水平上表达突变等位基因与野生型等位基因的差异。目前，我们不知道是否 DAEEs在蛋白质水平上导致随机的单等位基因表达，并涉及稳定或动态的等位基因 随着时间的推移，单元格中的表达式状态。此外，尚不清楚DAEE在大脑发育过程中何时出现， 特定细胞类型是否持续受到不同基因的影响，以及DAEEs是否可以与 形成表型效应的杂合突变。因此，我们建议进行一项探索性研究， 开始解决我们知识中的这些重要差距，并为未来的功能 以及DAEE在塑造心理健康方面的机制研究。目标1将确定表达谱 不同功能类别基因在大脑蛋白质和细胞水平上的DAEEs 表观遗传等位基因效应的发育模式，揭示单等位基因和双等位基因脑细胞群体 蛋白质水平和对单个细胞中稳定和动态等位基因状态的测试。目标2将确定 具有稳定的随机单等位基因表达效应的候选常染色体基因影响 特定行为和神经表型的杂合突变。我们的研究很有意义 因为它解决了我们知识中的根本差距，并将揭示新的、稳定的和/或动态的 表观遗传等位基因在蛋白质水平对脑基因表达的影响。测试结果将为测试奠定基础 特定的功能模型，有望揭示基因在等位基因和 大脑中的细胞水平会导致表型差异和精神疾病的风险。

PROJECT SUMMARY For reasons that are unclear, neuropsychiatric disorders are phenotypically variable and often the same gene is implicated in different disorders. Our limited understanding of the link between genotype and phenotype has stalled the development of improved diagnostics and therapeutics. An NIMH strategic priority to address this involves deepening our understanding of regulatory factors that alter gene expression and are important for brain processes relevant to mental illness. Little is known about allele-specific epigenetic effects that could interact with heterozygous genetic mutations to influence phenotypic variance and mental health. The goal of this study is to uncover novel epigenetic effects at the allele, protein and cellular level in the brain. In a recent publication in Neuron, we uncovered thousands of genes that differentially express their maternal and paternal alleles at the RNA level in vivo in a developmentally regulated manner in the mouse and primate brain. We refer to these phenomena as differential allele expression effects (DAEEs). DAEEs are not due to genetic variation or genomic imprinting and involve random monoallelic expression in subpopulations of brain cells. We found that DAEEs interact with heterozygous mutations to cause mosaics of monoallelic brain cells that differentially express mutant versus wildtype alleles at the RNA level. Currently, we do not know whether DAEEs result in random monoallelic expression at the protein level and involve stable or dynamic allelic expression states in a cell over time. Moreover, it is unclear when DAEEs arise during brain development, whether specific cell types are consistently impacted for different genes and whether DAEEs can interact with heterozygous mutations to shape phenotypic effects. Therefore, we propose an exploratory study that will begin to address these important gaps in our knowledge and set the foundations for future functional and mechanistic studies of DAEEs in shaping mental health. Aim 1 will determine the expression profiles of DAEEs at the protein and cellular level in the brain for different functional classes of genes with distinct developmental patterns of epigenetic allelic effects, revealing monoallelic and biallelic brain cell populations at the protein level and testing for stable versus dynamic allelic states in individual cells. Aim 2 will identify candidate autosomal genes with stable random monoallelic expression effects that shape the impact of heterozygous mutations on specific behavioral and neurological phenotypes. Our study is significant because it addresses fundamental gaps in our knowledge and will uncover novel stable and/or dynamic epigenetic allelic effects on brain gene expression at the protein level. The results will lay foundations to test specific functional models that are expected to reveal mechanisms by which gene regulation at the allele and cellular level in the brain contributes to phenotypic variance and risks for mental illness.