TRANSCRIPTIONAL REGULATION BY GEMININ

GEMININ 的转录调控

• 批准号: 8436889
• 负责人: Kristen L Kroll
• 金额: $ 35.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436889
• 关键词: Acetylation; Binding; Biochemical; Biological; Brain; Cells; Chromatin; Chromatin Remodeling Factor; Complex; Congenital Abnormality; Congenital neurologic anomalies; Consensus; Cues; Data; Defect; Development; EP300 gene; Embryo; Embryonic Development; Embryonic Nervous System; Epigenetic Process; Family; Foundations; Geminin; Gene Activation; Gene Expression; Genes; Genetic Engineering; Genomics; Human; In Vitro; Location; Maintenance; Medical; Modeling; Molecular; Mus; Mutation; Nervous system structure; Neuraxis; Neurons; Nodal; Nuclear Protein; Nucleoproteins; Patients; Pattern; Play; Polycomb; Procedures; Process; Property; Protocols documentation; Regulation; Regulator Genes; Repression; Role; Signal Transduction; Site; Skin; Source; Testing; Tissues; Transactivation; Transcriptional Regulation; Transplantation; Undifferentiated; Vertebrates; Work; Zinc Fingers; base; blastomere structure; cell type; chromatin remodeling; combinatorial; embryonic stem cell; genome wide association study; genome-wide; histone acetyltransferase; human disease; in vitro Model; induced pluripotent stem cell; intercellular communication; loss of function; nerve stem cell; nervous system disorder; neural precursor cell; neurodevelopment; neuroregulation; progenitor; programs; public health relevance; relating to nervous system; repaired; response; transcription factor

DESCRIPTION (provided by applicant): Undifferentiated neural precursor cells can be derived from embryonic stem cells or reprogrammed somatic (iPS) cells in unlimited quantities, have broad differentiation potential, can be modified by genetic engineering or clonally selected for particular properties and, for iPS cells, can be patient-matched to avoid immunological incompatibilities. Therefore, these cells are of high significance for in vitro modeling of human neurological diseases and for developing transplantation-based therapies to replace or stimulate repair of damaged tissue. Given the broad utility of these cells, we know surprisingly little about cell intrinsic regulatory networks that direct the initial acquisition of a neural fate and that maintain neural precursors in an undifferentiated state. This significantly limits our understanding of neural development and hampers efforts to compare and manipulate neural precursor cells derived from different starting cell sources or protocols. During vertebrate embryogenesis, Geminin and the Zic family of zinc finger transcription factors control the earliest cell intrinsic responses to neural induction and have essential roles in initial neural specification and maintenance of the undifferentiated state. Mutational analyses of these transcription factors supports their central roles in development and contribution to human disease: complete loss of Geminin results in early embryonic lethality in mice, while Zic1-4 mutations in humans cause a range of embryonic and nervous system malformations and neurological disorders. However, regulatory networks and mechanisms through which these transcription factors act remain largely unknown. Here, we will elucidate transcriptional programs and direct targets that they control at a genome-wide level and will use these data to construct regulatory networks underlying neural fate acquisition. We will test the hypothesis that Geminin is a central regulator of neural versus non-neural fate choice, through interactions with distinct epigenetic regulatory complexes. This work will define epigenetic regulatory mechanisms that direct the earliest aspects of embryonic cell fate acquisition. We will pursue the following Specific Aims: 1. Determine mechanisms by which Geminin activates neural gene expression to promote neural cell fate, 2. Define and compare the transcriptional regulatory networks through which the Zic transcription factors and Geminin control neural specification, and 3. Test the hypothesis that Geminin acts cooperatively with Polycomb to repress non-neural, mesendodermal gene expression during early fate acquisition of embryonic cells. Together, this work will define the regulatory networks controlling initial neural fate acquisition will identify new neural regulatory activities and modes of regulation, and will determine mechanisms through which several epigenetic regulators centrally control cell state and developmental potential during early fate acquisition. These data will fill a fundamental gap in our understanding of early cell fate acquisition. They will inform our understanding of birth defects and provide an essential foundation for manipulating these regulatory networks to control neural cell specification in many biological contexts.

描述（由申请人提供）：未分化的神经前体细胞可以无限量地来源于胚胎干细胞或重编程体细胞（iPS），具有广泛的分化潜力，可以通过基因工程修饰或克隆选择特定的特性，对于iPS细胞，可以与患者匹配以避免免疫不相容性。因此，这些细胞对于人类神经系统疾病的体外建模和开发基于移植的疗法以替代或刺激受损组织的修复具有重要意义。考虑到这些细胞的广泛用途，我们对它们的了解令人惊讶地少之又少。 指导神经命运的初始获得并维持神经前体处于未分化状态的细胞内在调节网络。这大大限制了我们对神经发育的理解，并阻碍了比较和操纵来自不同起始细胞来源或方案的神经前体细胞的努力。 在脊椎动物胚胎发生过程中，Geminin和Zic家族的锌指转录因子控制最早的细胞对神经诱导的内在反应，并在初始神经特化和维持未分化状态中发挥重要作用。这些转录因子的突变分析支持它们在发育和人类疾病中的核心作用：Geminin的完全丧失导致小鼠早期胚胎死亡，而人类Zic 1 -4突变导致一系列胚胎和神经系统畸形和神经系统疾病。然而，这些转录因子发挥作用的调控网络和机制在很大程度上仍然未知。在这里，我们将阐明转录程序和直接目标，他们控制在全基因组水平，并将使用这些数据来构建监管网络的神经命运收购。我们将通过与不同的表观遗传调控复合物的相互作用来检验这一假设，即Geminin是神经与非神经命运选择的中枢调控因子。这项工作将定义指导胚胎细胞命运获得的最早方面的表观遗传调控机制。 我们将追求以下具体目标：1。确定Geminin激活神经基因表达以促进神经细胞命运的机制，2.定义并比较Zic转录因子和Geminin控制神经特化的转录调控网络。检验以下假设：Geminin与Polycomb协同作用，在胚胎细胞的早期命运获取过程中抑制非神经、中内胚层基因表达。总之，这项工作将定义控制初始神经命运收购的监管网络，将确定新的神经调节活动和调节模式，并将确定机制，通过几个表观遗传调节集中控制细胞状态和发育潜力在早期命运收购。这些数据将填补我们对早期细胞命运获得的理解的根本空白。它们将告知我们对出生缺陷的理解，并为操纵这些调控网络以控制许多生物学背景下的神经细胞规范提供必要的基础。