Regulation of Hoxa1 Gene Expression in Mouse Embryonic Stem Cells

小鼠胚胎干细胞中 Hoxa1 基因表达的调控

• 批准号: 8879897
• 负责人: Eduardo Martinez-Ceballos
• 金额: $ 33.16万
• 依托单位: SOUTHERN UNIV A&M COL BATON ROUGE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879897
• 关键词: Agonist; Alleles; Antibodies; Area; Binding; Binding Sites; Brain; Cell Culture Techniques; Cell physiology; Cells; Central Nervous System Diseases; ChIP-on-chip; Code; DNA Binding; Data; Defect; Development; Developmental Biology; Disease; Embryo; Embryonic Development; Family; Family member; Feedback; Gene Expression; Gene Expression Regulation; Genes; Goals; Homeobox; Homeostasis; Homologous Gene; Human; Laboratories; Light; Maintenance; Malignant Neoplasms; MicroRNAs; Molecular; Mus; Mutation; Neural Crest; Neuronal Differentiation; Oncogenes; Organ; Organogenesis; Pattern; Play; Proteins; Proteomics; Regulation; Replacement Therapy; Repression; Research Personnel; Role; Signal Pathway; Signal Transduction; Structure; Tissues; Tretinoin; Vertebrates; Work; anticancer research; base; cranium; embryonic stem cell; hindbrain; monolayer; neonatal death; novel; overexpression; public health relevance; retinoic acid receptor beta 2; transcription factor; tumorigenesis

 DESCRIPTION (provided by applicant): Regulation of Hoxa1 Gene Expression in Mouse Embryonic Stem Cells The homeobox (Hox) family of transcription factors comprises important regulators of embryonic patterning and organogenesis. Inactivation in mice of both alleles of the Hoxa1, a Hox family member, results in numerous developmental defects, including hindbrain deficiencies and abnormal skull ossification, and ultimately, in neonatal death. These observations emphasize the importance of this gene in the proper development of the early brain and neural crest- derived structures. In humans, mutations in this gene have been described in association with various Central Nervous System (CNS) disorders and its overexpression has been associated with cancer development. Thus, a strict control of Hoxa1 gene expression is required for proper cellular function and embryonic development. Although the relevance of Hoxa1 during embryonic development has been recognized for over two decades, little is known about the factors that regulate the expression of this important TF. In this work, we present preliminary data that suggests a role for the retinoic acid receptor beta 2 (RARb2) as a negative regulator of Hoxa1 gene expression in mouse Embryonic Stem (ES) cells. Furthermore, we have performed ChIP-on-chip analyses for Hoxa1 and identified a putative Hoxa1 binding site in the Hoxa1 coding region, which suggests the presence of a novel autoregulatory mechanism for this TF. Thus, these preliminary results form the basis of the specific aims proposed in this project. Specific Aim 1 will investigate the regulation of Hoxa1 gene expression at the transcriptional level. Specific Aim 2 will investigate the effect of factors that regulate Hoxa1 expression at the posttranscriptional level. The mechanism of Hoxa1 feedback loop of gene regulation will be investigated in Specific Aim 3. In summary, the goal of the proposed study is to shed light on the molecular mechanism by which the expression of Hoxa1 is regulated in mouse ES cells. The results from these studies will be of relevance to the areas of Developmental Biology, Organ and Tissue Replacement, and Cancer Research, among others.

 描述（由申请人提供）：小鼠胚胎干细胞中Hoxa1基因表达的调节同源盒（Hox）转录因子家族包含胚胎模式和器官发生的重要调节因子。小鼠体内 Hoxa1（Hox 家族成员）的两个等位基因失活会导致许多发育缺陷，包括后脑缺陷和异常颅骨骨化，并最终导致新生儿死亡。这些观察结果强调了该基因在早期大脑和神经嵴衍生结构的正常发育中的重要性。在人类中，该基因的突变已被描述与各种中枢神经系统（CNS）疾病相关，并且其过度表达与癌症的发展有关。因此，严格控制 Hoxa1 基因表达对于正常的细胞功能和胚胎发育是必需的。尽管二十多年来人们已经认识到 Hoxa1 在胚胎发育过程中的相关性，但人们对调节这一重要 TF 表达的因素知之甚少。在这项工作中，我们提供了初步数据，表明视黄酸受体 β2 (RARb2) 作为小鼠胚胎干 (ES) 细胞中 Hoxa1 基因表达的负调节因子。此外，我们对 Hoxa1 进行了 ChIP-on-chip 分析，并在 Hoxa1 编码区鉴定了一个假定的 Hoxa1 结合位点，这表明该 TF 存在一种新的自动调节机制。因此，这些初步结果构成了该项目提出的具体目标的基础。具体目标 1 将研究转录水平上 Hoxa1 基因表达的调控。具体目标 2 将调查因素的影响 在转录后水平调节 Hoxa1 表达。 Hoxa1 基因调节反馈环路的机制将在具体目标 3 中进行研究。总之，本研究的目的是阐明小鼠 ES 细胞中 Hoxa1 表达调节的分子机制。这些研究的结果将与发育生物学、器官和组织替代以及癌症研究等领域相关。

项目成果

RARβ2-dependent signaling represses neuronal differentiation in mouse ES cells.

RARβ2 依赖性信号传导抑制小鼠 ES 细胞中的神经元分化。

• DOI: 10.1016/j.diff.2017.11.002
• 发表时间: 2017
• 期刊: Differentiation; research in biological diversity
• 作者: Kona,SriL;Shrestha,Amita;Yi,Xiaoping;Joseph,Serenthia;Barona,HumbertoMunoz;Martinez-Ceballos,Eduardo
• 通讯作者: Martinez-Ceballos,Eduardo