The Nature and Function of Genomic Imprinting in Monoaminergic Neurons

单胺能神经元基因组印记的性质和功能

• 批准号: 9079842
• 负责人: Chris Gregg
• 金额: $ 37.25万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-04 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079842
• 关键词: Affect; Alleles; Animal Behavior; Animals; Anxiety; Anxiety Disorders; Architecture; Behavior; Behavioral Assay; Brain; Brain region; Carboxy-Lyases; Cells; Data; Disease; Dopa; Dopamine; Epigenetic Process; Exhibits; Female; Functional disorder; Gene Expression; Genes; Genetic; Genomic Imprinting; Genomic approach; Hybrids; Image; Immunohistochemistry; Individual; Inherited; Label; Lead; Link; Major Depressive Disorder; Mental Health; Mental disorders; Methods; Mus; Mutant Strains Mice; Mutation; Nature; Neurons; Neurotransmitters; Norepinephrine; Parents; Physiology; Population; Public Health; Reporter; Research; Research Priority; Risk; Role; Schizophrenia; Serotonin; Signal Transduction; Site; Social Behavior; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Tyrosine 3-Monooxygenase; Variant; base; behavior influence; behavior test; cell type; genetic risk factor; genetic variant; imprint; improved; innovation; male; maternal imprint; monoamine; motivated behavior; mutant; neuropsychiatric disorder; novel; offspring; paternal imprint; public health relevance; therapeutic target; transcriptome; transcriptomics

 DESCRIPTION (provided by applicant): Many variants that influence the risk for neuropsychiatric disorders are heterozygous in the affected individual. Genomic imprinting, which is a heritable epigenetic mechanism that results in preferential expression of the maternal or paternal allele for some genes, can worsen the effects of heterozygous mutations by silencing the healthy allele, leading to expression of only the mutant allele. Canonical imprinting involves complete silencing of one parent's allele. The authors recently discovered hundreds of genes that exhibit a maternal or paternal allele bias in the brain. They refer to this as noncanonical imprinting. Using a novel method, the authors have evidence that noncanonical imprinting effects detected at the tissue level involve allele-silencing in subpopulations of neurons in the brain. They further found that noncanonical imprinting significantly influences the impact of heterozygous mutations on offspring behavior depending on the parental origin of the mutation. Thus, the results indicate the existence of highly cell-type specific imprinting effects n the brain. Currently, it is unknown which neuronal populations are involved, how specific behaviors are impacted, and whether additional genes are imprinted in specific neuron types. Noncanonical imprinting was found to influence the expression of tyrosine hydroxylase (Th) and dopa decarboxylase (Ddc), two genes essential for the synthesis of the monoamine neurotransmitters dopamine, noradrenaline and serotonin. Dysfunction of the monoaminergic systems occurs in anxiety disorders, major depression, bipolar, schizophrenia and other mental disorders. The proposed study will test the hypothesis that noncanonical imprinting causes allele- silencing effects in subpopulations of monoaminergic neurons to regulate important aspects of behavior and physiology. In aim 1, anatomically-defined subpopulations of monoaminergic neurons that are enriched for Th and Ddc imprinting effects will be defined in the male and female brain using transgenic mice that express egfp and tdTomato reporters from the maternal and paternal alleles, respectively. In aim 2, the function(s) of noncanonical imprinting effects influencing monoaminergic neurons will be defined using a battery of behavioral assays to compare mutant mice with maternally versus paternally inherited deletions in Th and Ddc. Finally, in aim 3, imprinting effects in monoaminergic neurons will be comprehensively profiled using single-cell RNASeq on EGFP+ neurons purified from transgenic F1 hybrid offspring. Hybrid offspring will be generated from reciprocal matings of Ddc::egfp transgenic reporter mice (Aim 1) on the C57BL/6J x CastEiJ genetic backgrounds. Polymorphic sites in the F1 hybrids will reveal allelic expression in the RNASeq data. Overall, the study will define the cellular nature and function of imprinting effects in monoaminergic neurons in the brain and establish noncanonical imprinting as an important epigenetic phenomenon that influences the function and allelic architecture of monoaminergic circuits.

 描述（由申请人提供）：影响神经精神疾病风险的许多变异在受影响的个体中是杂合的，这是一种可遗传的表观遗传机制，导致某些基因优先表达母本或父本等位基因，可能会使病情恶化。通过沉默健康等位基因，导致仅表达突变等位基因，从而产生杂合突变的影响。 作者最近发现了数百个在大脑中表现出母系或父系等位基因偏差的基因，他们将其称为非规范印记。组织水平涉及大脑神经元亚群的等位基因沉默，他们进一步发现，根据父母的起源，非规范印记显着影响杂合突变对后代行为的影响。因此，结果表明大脑中存在高度细胞类型特异性的印记效应，目前尚不清楚哪些神经群体参与其中，特定行为如何受到影响，以及是否有其他基因印记在特定的神经类型中。研究发现，非经典印记会影响酪氨酸羟化酶 (Th) 和多巴脱羧酶 (Ddc) 的表达，这两个基因对于合成单胺神经递质多巴胺、去甲肾上腺素至关重要焦虑症、重度抑郁症、躁郁症、精神分裂症和其他精神障碍中会出现单胺能系统功能障碍。这项研究将检验非规范印记在单胺能神经元亚群中引起等位基因沉默效应以调节行为的重要方面的假设。在目标 1 中，解剖学上定义的单胺能神经元亚群富含 Th 和 Ddc 印记效应。将使用分别表达来自母本和父本等位基因的egfp和tdTomato生产者的转基因小鼠在雄性和雌性大脑中定义。在目标2中，将使用一组来定义影响单胺能神经元的非规范印记效应的功能。最后，在目标 3 中，将使用 Th 和 Ddc 全面分析单胺能神经元的印记效应。从转基因 F1 杂交后代纯化的 EGFP+ 神经元上的单细胞 RNASeq 将由 F1 杂交后代中 Ddc::egfp 转基因报告小鼠（目标 1）的相互交配产生。总体而言，该研究将揭示大脑单胺能神经元印记效应的细胞性质和功能。并将非规范印记确立为一种重要的表观遗传现象，影响单胺能回路的功能和等位基因结构。