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

• 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
• 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

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控制脊椎动物中枢神经系统内基因表达和细胞命运规范中的作用和调节。 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。 以这种能力，调解员可以通过激活剂和阻遏蛋白引导调节信号，以影响控制多种生理过程的基因表达程序的变化，包括细胞生长和稳态，发育和分化。 MED12是由XQ13编码的230 kDa介体亚基，通过选择性调节神经元基因表达在神经元发育中起着至关重要的作用。 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通过选择性基因调节控制神经元分化的分子碱基以及病理序列改变会影响Med12功能的手段，导致行为和认知缺陷仍尚待阐明。 在这方面，我们最近确定了由Re1沉默转录因子/神经元限制性沉默因子（静电/NRSF）施加的表观遗传沉默所需的Med12界面与G9A组蛋白甲基转移酶之间的功能相互作用，这是神经元抑制神经元中神经元的关键决定性的决定性的决定性的决定性的确定性。 值得注意的是，我们发现Med12中的错义突变负责两种XLMR疾病，FG综合征和Lujan综合征，破坏了其静止的特异性核心压力功能，从而将依赖的依赖性神经元基因抑制与人类中的高阶认知功能联系起来。 由于我们最近的研究暗示了依赖静止的神经元基因抑制在神经祖细胞分化的表观遗传限制中，因此我们的发现提供了一种可能的表观遗传学观点，可以通过改变神经元发育来解释MED12在XLMR病因中的作用。 因此，我们假设Med12中XLMR相关的突变破坏了对神经元基因表达和神经祖细胞分化的静止施加的表观遗传限制。 为了提供这一假设的支持，我们提出以下旨在解释Med12/介体在静止依赖性表观遗传抑制神经元基因表达和分化中的作用和病理意义：（1）阐明Med12/介体在静止依赖性依赖依赖的神经元基因沉默中Med12/介体的机械基础； （2）阐明Med12/介体在依赖静止的神经元基因表达和神经祖细胞中分化的作用和调节； （3）阐明了Med12中与XLMR相关突变对神经祖细胞中神经元基因表达和分化的静止抑制的影响和机制。 我们希望这些研究对神经系统疾病的细胞替代疗法以及XLMR的病因具有重要的人类健康影响。 公共卫生相关性：我们希望这些研究对人类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具有重要意义。 首先，本文提出的研究以阐明Med12/介体的机制（AIM 1）和调节（AIM 2）/介体控制神经元基因表达和分化，将破坏新的地面并阐明神经干细胞生物学的基本方面，这对于指导基于基于细胞的细胞治疗方法至关重要。 其次，本文提出的研究以评估XLMR相关的MED12中与神经元基因抑制和神经干细胞分化相关的基本生化特性以及功能相互作用的影响（AIM 3）应揭示有关XLMR病因的新机械洞察力，并可能确定XLMR的病因，并可能确定新的apection and apection cornepection或ReSedial iNCEDIALECEDIAL或RESEDIALECEDIAL。