Thyroid hormone regulates DNA methylation in the developing brain through direct modulation of the DNA methyltransferase 3a gene

甲状腺激素通过直接调节 DNA 甲基转移酶 3a 基因来调节发育中大脑的 DNA 甲基化

• 批准号: 8995718
• 负责人: ROBERT J DENVER
• 金额: $ 19.07万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995718
• 关键词: Adult; Autistic Disorder; Basic Science; Behavior Disorders; Brain; CCND1 gene; Cell Cycle; Cell Cycle Arrest; Cell Cycle Regulation; Cell Differentiation process; Cell Proliferation; Cell model; Cerebral cortex; Cognitive deficits; Complex; Cretinism; Cyclin D1; Cytosine; DNA; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; DNA Sequence; Data; Development; Disease; E2F transcription factors; Endocrine Disruptors; Enzymes; Epigenetic Process; Exposure to; Gene Expression; Gene Targeting; Genes; Genome; Goals; Growth; Health; Hormones; Human; Human Development; Introns; Knock-out; Lead; Life; Maintenance; Malignant Neoplasms; Mediating; Methylation; Modification; Molecular; Mus; Neonatal; Neuraxis; Neuroglia; Neurologic; Neurons; Nucleic Acid Regulatory Sequences; Play; Process; Protein Isoforms; Psyche structure; Regulation; Research; Role; Schizophrenia; Signal Transduction; Testing; Thyroid Gland; Thyroid Hormone Receptor; Thyroid Hormones; Work; autism spectrum disorder; base; embryo/fetus; fetal; gene function; histone modification; hormone deficiency; hormone regulation; hormone response element; human disease; in vivo; knock-down; methylation pattern; nervous system disorder; neuroblast; neuroblastoma cell; postnatal; promoter; receptor; research study; thyroid disruption

 DESCRIPTION (provided by applicant): Epigenetic modifications, which result in heritable changes in gene function that do not involve changes to the DNA sequence, play central roles in human brain development. Dynamic regulation of DNA methylation by de novo DNA methyltransferases (Dnmts) is implicated in the control of neuronal and glial cell differentiation. We recently discovered that the Dnmt3a gene is a direct thyroid hormone (TH) receptor (TR) target in mouse brain. Postembryonic brain development is critically dependent on thyroid hormone (TH); TH deficiency during fetal and neonatal periods of human development leads to a condition of severe mental and growth retardation known as cretinism. We hypothesize that TH regulation of Dnmt3a plays a pivotal role in normal neurological development, since recent evidence supports that dynamic postnatal regulation of Dnmt3a may be essential for establishing DNA methylation patterns in the developing brain. In the proposed research we will: 1) Investigate the regulation of the Dnmt3a gene in mouse brain in vivo by TH throughout early postnatal development. We will investigate TR recruitment to the Dnmt3a locus, and histone modifications induced by TH. We will directly test whether TH response elements that we identified are required for TH regulation of the Dnmt3a gene. 2) Investigate a role for Dnmt3a in TH-dependent neural cell cycle arrest and differentiation. We will investigate whether cell cycle arrest is mediated by Dnmt3a methylation of the promoter of the cell cycle control gene Cyclin D1, and possibly other E2F target genes. For these experiments we will use mouse neuronal cell models that expresses the ß1 isoform of TR. Proper exit from the cell cycle, cell differentiation and the maintenance of cell cycle arrest is essential for normal development. Disruption of these processes in the embryo and fetus can lead to abnormal development; disruption in the adult can lead to cancer and other disease. Thyroid hormone plays a central role in cell cycle exit and cell differentiation in the central nervous system. Several lines of evidence support that Cyclin D1 is directly regulated by Dnmt3a-mediated DNA methylation. We hypothesize that TH regulation of DNA methylation of regulatory regions of cell cycle control genes plays a key role in this process. Successful completion of the proposed research will lead to advances in our understanding of the mechanisms by which DNA methylation is regulated during development, and the roles of TH-dependent DNA methylation in cell proliferation and differentiation.

 描述（由申请人提供）：表观遗传修饰在人脑发育中发挥核心作用，表观遗传修饰导致基因功能的可遗传变化，但不涉及DNA序列的变化。通过从头DNA甲基转移酶（Dnmts）对DNA甲基化的动态调节涉及神经元和神经胶质细胞分化的控制。 我们最近发现Dnmt 3a基因是小鼠脑中甲状腺激素（TH）受体（TR）的直接靶点。胚胎期后的大脑发育严重依赖于甲状腺激素（TH）;在胎儿和新生儿期的人类发育过程中，TH缺乏会导致严重的智力和生长迟缓，称为克汀病。我们假设TH调节Dnmt 3a在正常神经发育中起着关键作用，因为最近的证据支持Dnmt 3a的动态产后调节可能是在发育中的大脑中建立DNA甲基化模式所必需的。本研究主要包括以下几个方面：1）在小鼠出生后早期发育过程中，研究TH对小鼠脑内Dnmt 3a基因的调控。我们将研究TR招募到Dnmt 3a位点，和TH诱导的组蛋白修饰。我们将直接测试我们鉴定的TH应答元件是否是Dnmt 3a基因的TH调节所需的。2)研究Dnmt 3a在TH依赖性神经细胞周期阻滞和分化中的作用。我们将研究细胞周期阻滞是否由细胞周期控制基因Cyclin D1启动子的Dnmt 3a甲基化介导，以及可能的其他E2 F靶基因。对于这些实验，我们将使用表达TR β 1亚型的小鼠神经元细胞模型。细胞周期的适当退出、细胞分化和细胞周期停滞的维持对于正常发育至关重要。这些过程在胚胎和胎儿中的破坏可能导致发育异常;在成人中的破坏可能导致癌症和其他疾病。甲状腺激素在中枢神经系统的细胞周期退出和细胞分化中起核心作用。几条证据支持细胞周期蛋白D1直接受Dnmt 3a介导的DNA甲基化调控。我们推测TH调控细胞周期调控基因调控区的DNA甲基化在这一过程中起着关键作用。这项研究的成功完成将使我们进一步了解DNA甲基化在发育过程中的调控机制，以及TH依赖的DNA甲基化在细胞增殖和分化中的作用。