Neuroepigenetic regulation of social status

社会地位的神经表观遗传调控

• 批准号: 8384195
• 负责人: RUSSELL D FERNALD
• 金额: $ 23.55万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8384195
• 关键词: Adopted; Adult; African; Animal Model; Animals; Area; Base Pairing; Behavior; Behavioral; Behavioral Paradigm; Brain; Categories; Chemicals; Cichlids; Color; Competence; DNA; DNA Methylation; DNA Sequence; Data; Depression and Suicide; Development; Epigenetic Process; Event; Fishes; Future; Gene Expression; Gene Expression Profile; Genes; Genome; Genomics; Gonadotropin Hormone Releasing Hormone; Grant; Human; Lead; Life; Malignant Neoplasms; Maps; Methods; Methylation; Modification; Molecular; Neurons; Nucleotides; Optics; Organism; Outcome; Pathway Analysis; Pattern; Phenotype; Physical environment; Physiological; Plastics; Play; Reagent; Regulation; Relative (related person); Resolution; Role; Signal Transduction; Social Environment; Social Interaction; Social status; System; Testing; Time; Vertebrates; Weight; Zebularine; biological systems; bisulfite; demethylation; experience; gene environment interaction; genome sequencing; imprint; in vivo; innovation; insight; male; mature animal; neural circuit; novel; receptor; relating to nervous system; reproductive; reproductive axis; research study; response; social; trait

DESCRIPTION (provided by applicant): An organism's DNA sequence remains fundamentally unchanged over an animal's life so that long term phenotypic and behavioral changes are thought to result from modifications in neural circuits. Recently, however, another, complementary mechanism, DNA methylation, has been implicated in these changes. DNA methylation, previously thought to act only during the imprinting of genes during development, can act quickly and reversibly on gene expression patterns in adult organisms. We propose novel experiments to test whether and where DNA methylation can lead to dramatic phenotypic and behavioral changes in vivo using a well suited cichlid fish as an animal model. In this species, A. burtoni, males exist in either of two distinct, reversible phenotypes: reproductively competent dominant (D) males and reproductively incompetent non-dominant (ND) males. The switch between phenotypes is a consequence of the social environment and produce physiological changes within minutes, ultimately resulting in remodeling of the reproductive axis. The main regulator of reproductive competence, gonadotropin releasing hormone (GnRH1) containing neurons in the pre-optic area (POA) of the brain, change their size and connectivity and there are numerous other modifications from body coloration to molecular regulation in receptor abundance. We have shown that we can induce these dramatic changes in phenotype from ND > D by global methylation and conversely from D > ND by global demethylation. In the proposed experiments, we will make genomic maps of methylation at single-base-pair resolution by combining bisulfite treatment of genomic DNA with ultra-high-throughput sequencing (Illumina Genome Analyser). The methylation state of all fish due to developmental events will be shared. However, we will identify methylation events associated with each distinct phenotype in response to natural behavioral encounters or as a result of treatment with methylation-regulating agents. These novel results will provide important insights into the relationship between methylation and behavioral phenotype. We will identify where in the brain the subset of genes implicated in social status change are located. We will also map the time course of methylation changes relative to phenotype change to discover whether these are simultaneous or sequential. The long-term objectives are to understand how methylation interacts with known brain circuitry to co-regulate behavior. The demethylating reagent we use, zebularine, is used to treat cancer and our analysis will be the first to provide a behavioral analysis of its effects. PUBLIC HEALTH RELEVANCE: Epigenetic changes in gene expression caused by methylation have been implicated in suicide, depression and other undesirable behavioral outcomes. Understanding how gene methylation alters behavior will have importance for a wide range of human behaviors.

描述（由申请人提供）：生物体的 DNA 序列在动物的一生中基本保持不变，因此长期的表型和行为变化被认为是由神经回路的改变引起的。然而最近，另一种补充机制——DNA甲基化——与这些变化有关。 DNA甲基化以前被认为只在发育过程中的基因印记过程中起作用，但它可以快速且可逆地作用于成年生物体的基因表达模式。我们提出了新的实验来测试 DNA 甲基化是否以及在哪里可以导致体内显着的表型和行为变化，使用非常适合的丽鱼作为动物模型。在该种 A. burtoni 中，雄性存在两种不同的、可逆的表型中的任何一种：具有生殖能力的显性 (D) 雄性和生殖能力不强的非显性 (ND) 雄性。表型之间的转换是社会环境的结果，并在几分钟内产生生理变化，最终导致生殖轴的重塑。生殖能力的主要调节剂促性腺激素释放激素 (GnRH1) 含有大脑视前区 (POA) 中的神经元，会改变其大小和连接性，并且还有许多其他修饰，从身体颜色到受体丰度的分子调节。我们已经证明，我们可以通过全局甲基化诱导 ND > D 的表型显着变化，反之，通过全局去甲基化诱导 D > ND 表型的显着变化。在拟议的实验中，我们将通过将基因组 DNA 的亚硫酸氢盐处理与超高通量测序（Illumina Genome Analyser）相结合，以单碱基对分辨率绘制甲基化基因组图谱。所有鱼类由于发育事件而产生的甲基化状态将被共享。然而，我们将识别与每种不同表型相关的甲基化事件，以响应自然行为遭遇或作为甲基化调节剂治疗的结果。这些新颖的结果将为甲基化与行为表型之间的关系提供重要的见解。我们将确定与社会地位变化有关的基因子集位于大脑中的哪个位置。我们还将绘制甲基化变化相对于表型变化的时间过程，以发现这些变化是同时的还是顺序的。长期目标是了解甲基化如何与已知的大脑回路相互作用以共同调节行为。我们使用的去甲基化试剂zebularine用于治疗癌症，我们的分析将是第一个对其效果进行行为分析的分析。 公共卫生相关性：甲基化引起的基因表达的表观遗传变化与自杀、抑郁和其他不良行为结果有关。了解基因甲基化如何改变行为对于广泛的人类行为具有重要意义。