Mediator and epigenetic control of neuronal gene expression and differentiation

神经元基因表达和分化的介质和表观遗传控制

基本信息

批准号：
8015297
负责人：
THOMAS G BOYER
金额：
$ 36.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-07 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8015297
关键词：
Affect Area Behavioral Biochemical Biological Process Cell Differentiation process Cells Cognitive Defect Development Epigenetic Process Etiology FG Syndrome G9a histone methyltransferase Gene Expression Gene Expression Regulation Gene Mutation Gene Silencing Gene Targeting Genes Genetic Transcription Genetic Variation Goals Health Homeostasis Human Link Mediator of activation protein Missense Mutation Molecular Mutation Nervous system structure Neuraxis Neuroglia Neuronal Differentiation Neurons Pathologic Physiological Processes Play Property RE1-silencing transcription factor RNA Polymerase II Regulation Replacement Therapy Repression Repressor Proteins Research Personnel Role Schedule Signal Transduction Syndrome Therapeutic X-Linked Mental Retardation Xq13 base cell fate specification cell growth cognitive function gene repression insight nerve stem cell nervous system disorder neuron development neuropsychiatry programs prospective public health relevance stem cell biology stem cell differentiation transcription factor

项目摘要

DESCRIPTION (provided by investigator): Our long-term goal is to understand the role and regulation of Mediator in the control of gene expression and cell fate specification within the vertebrate central nervous system. Mediator is a multiprotein interface between gene-specific transcription factors and the eukaryotic RNA polymerase II general transcription machinery. In this capacity, Mediator serves to channel regulatory signals from activator and repressor proteins to affect changes in gene expression programs that control diverse physiological processes, including cell growth and homeostasis, development, and differentiation. MED12, an Xq13-encoded 230 kDa Mediator subunit, plays an essential role in neuronal development through selective regulation of neuronal gene expression. Genetic variation in MED12 has been linked to neuropsychiatric illness and X-linked mental retardation (XLMR). However, the molecular bases by which MED12 controls neuronal differentiation through selective gene regulation and the means by which pathologic sequence alterations impact MED12 function leading to behavioral and cognitive defects remain to be clarified. In this regard, we recently identified a functional interaction between the MED12 interface in Mediator and G9a histone methyltransferase required for epigenetic silencing imposed by the RE1 silencing transcription factor/neuron restrictive silencing factor (REST/NRSF), a key determinant of neuronal fate that suppresses neuronal gene expression in non-neuronal and neural progenitor cells. Notably, we found that missense mutations in MED12 responsible for two XLMR disorders, FG syndrome and Lujan syndrome, disrupt its REST-specific corepressor function, thus linking REST-dependent neuronal gene repression with higher-order cognitive function in humans. Because our recent studies implicate REST-dependent neuronal gene repression in epigenetic restriction of neural progenitor cell differentiation, our findings provide a possible epigenetic perspective to explain the role of MED12 in the etiology of XLMR through altered neuronal development. Thus, we hypothesize that XLMR- associated mutations in MED12 disrupt REST-imposed epigenetic restrictions on neuronal gene expression and neural progenitor cell differentiation. To provide support for this hypothesis, we propose the following aims to decipher the role and pathologic implications of MED12/Mediator in REST-dependent epigenetic suppression of neuronal gene expression and differentiation: (1) Elucidate the mechanistic basis of MED12/Mediator in REST-dependent extra-neuronal gene silencing; (2) Elucidate the role and regulation of MED12/Mediator in REST-dependent suppression of neuronal gene expression and differentiation in neural progenitor cells; (3) Elucidate the impact and mechanism of XLMR-associated mutations in MED12 on REST- dependent suppression of neuronal gene expression and differentiation in neural progenitor cells. We expect these studies to have important human health implications for cell replacement therapy in neurological disease as well as the etiology of XLMR. PUBLIC HEALTH RELEVANCE: We expect these studies to have important implications for cell replacement therapy in neurological disease as well as the etiology of developmental and cognitive defects in humans. First, studies proposed herein to elucidate the mechanism (Aim 1) and regulation (Aim 2) of MED12/Mediator in control of neuronal gene expression and differentiation are expected to break new ground and illuminate fundamental aspects of neural stem cell biology that will be essential to guide prospective cell-based therapeutic approaches to repopulate damaged or diseased areas of the nervous system. Second, studies proposed herein to evaluate the impact of XLMR-associated mutations in MED12 on its basic biochemical properties and functional interactions relevant to neuronal gene repression and neural stem cell differentiation (Aim 3) should reveal new mechanistic insight concerning the etiology of XLMR and possibly identify new avenues for therapeutic or remedial intercession.

描述（由研究者提供）：我们的长期目标是了解介体在脊椎动物中枢神经系统内基因表达和细胞命运规范控制中的作用和调节。介体是基因特异性转录因子和真核 RNA 聚合酶 II 通用转录机制之间的多蛋白界面。通过这种能力，Mediator 可以引导来自激活蛋白和阻遏蛋白的调节信号，以影响控制多种生理过程（包括细胞生长和稳态、发育和分化）的基因表达程序的变化。 MED12 是 Xq13 编码的 230 kDa 介导亚基，通过选择性调节神经元基因表达，在神经元发育中发挥重要作用。 MED12 的遗传变异与神经精神疾病和 X 连锁智力低下 (XLMR) 有关。然而，MED12 通过选择性基因调控控制神经元分化的分子基础以及病理序列改变影响 MED12 功能导致行为和认知缺陷的方式仍有待阐明。在这方面，我们最近发现了 Mediator 中的 MED12 接口和 G9a 组蛋白甲基转移酶之间的功能相互作用，这是 RE1 沉默转录因子/神经元限制性沉默因子 (REST/NRSF) 施加的表观遗传沉默所需的，REST/NRSF 是抑制神经元命运的关键决定因素。非神经元和神经祖细胞中的神经元基因表达。值得注意的是，我们发现导致两种 XLMR 疾病（FG 综合征和 Lujan 综合征）的 MED12 错义突变破坏了其 REST 特异性辅抑制子功能，从而将 REST 依赖性神经元基因抑制与人类高阶认知功能联系起来。由于我们最近的研究表明 REST 依赖性神经元基因抑制与神经祖细胞分化的表观遗传限制有关，因此我们的研究结果提供了一个可能的表观遗传视角，以解释 MED12 通过改变神经元发育在 XLMR 病因学中的作用。因此，我们假设 MED12 中的 XLMR 相关突变破坏了 REST 对神经元基因表达和神经祖细胞分化施加的表观遗传限制。为了支持这一假设，我们提出以下目标，以破译MED12/Mediator在神经元基因表达和分化的REST依赖性表观遗传抑制中的作用和病理意义：（1）阐明MED12/Mediator在REST-中的机制基础依赖性神经元外基因沉默；（2）阐明MED12/Mediator在神经祖细胞中REST依赖性抑制神经元基因表达和分化中的作用和调节； (3)阐明MED12中XLMR相关突变对神经祖细胞中神经元基因表达和分化的REST依赖性抑制的影响和机制。我们预计这些研究将对神经系统疾病的细胞替代疗法以及 XLMR 的病因学产生重要的人类健康影响。公共健康相关性：我们预计这些研究将对神经系统疾病的细胞替代疗法以及人类发育和认知缺陷的病因学产生重要影响。首先，本文提出的研究旨在阐明 MED12/Mediator 控制神经元基因表达和分化的机制（目标 1）和调节（目标 2），预计将开辟新领域并阐明神经干细胞生物学的基本方面，这将是至关重要的指导基于细胞的前瞻性治疗方法来重新填充神经系统受损或患病区域。其次，本文提出的研究旨在评估 MED12 中 XLMR 相关突变对其基本生化特性以及与神经元基因抑制和神经干细胞分化相关的功能相互作用（目标 3）的影响，应揭示有关 XLMR 病因学的新机制见解，并可能确定治疗或补救代祷的新途径。