Regulating transcription of the key neural lineage driver ASCL1 - Diversity Administrative Supplement

调节关键神经谱系驱动 ASCL1 的转录 - Diversity Administration Supplement

• 批准号: 10405391
• 负责人: Jane E Johnson
• 金额: $ 3.86万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405391
• 关键词: ASCL1 gene; Administrative Supplement; Autonomic nervous system; Brain; Cell Culture Techniques; Cells; Complex; Development; Developmental Gene; Disease; Fibroblasts; Future; Genes; Genetic Transcription; Genome; Genomics; Goals; Human; Knowledge; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Olfactory Epithelium; Regulation; Regulatory Element; Retina; Signal Transduction; Spinal Cord; Technology; Testing; Transcriptional Regulation; Untranslated RNA; cell type; in vitro Model; in vivo; in vivo Model; insight; interest; neurodevelopment; neurogenesis; neuropsychiatric disorder; postnatal; progenitor; relating to nervous system; sensory system; success; transcription factor

The bHLH transcription factor ASCL1 (HASH1/MASH1) is essential for neuronal differentiation and sub-type specification of multiple neuronal cell-types throughout the brain, spinal cord, and autonomic nervous system, as well as cells in sensory systems such as the retina and olfactory epithelia. ASCL1 function is balanced with NOTCH signaling activity to control progenitor proliferation and differentiation. ASCL1 has also been identified as a pioneering factor and a key component of cocktails directly reprogramming fibroblasts to neurons. With these important functions attributed to ASCL1, and its requirement for controlled spatial and temporal expression in vivo for viability postnatally, it is surprising how little is known about regulation of ASCL1 gene transcription. This gap in knowledge reflects past technical challenges in identifying and manipulating cis-regulatory elements (REs) found at large distances from the gene of interest. REs functioning at long-distances to control key developmental genes are being discovered using advances in technologies that can interrogate and manipulate the spatial genome. Here we will exploit these technologies to gain much needed insights into transcriptional control of ASCL1 using cell culture and in vivo models of neural development. Each model has a particular strength that allows unique aspects of ASCL1 regulation to be uncovered. Aims include identifying and testing functions of long-range REs controlling ASCL1 during neuronal differentiation in mouse (in vivo) and human (in vitro) models. Success in these aims will provide functional non-coding regulatory sequences controlling ASCL1 expression. This is important for future projects to identify molecular components of the signaling complexes working through these REs to reach the goal of providing an understanding of how a key lineage defining transcriptional regulator is controlled during development and disease.

bHLH转录因子ASCL 1（HASH 1/MASH 1）是神经元分化所必需的 和多种神经元细胞类型的子类型说明， 自主神经系统，以及感觉系统中的细胞，如视网膜和嗅觉 上皮细胞ASCL 1功能与NOTCH信号传导活性平衡以控制祖细胞 增殖和分化。ASCL 1也被认为是一个开创性的因素， 鸡尾酒成分直接将成纤维细胞重编程为神经元。与这些重要 ASCL 1的功能及其对受控空间和时间的要求 然而，令人惊讶的是，关于在出生后的存活率中的体内表达的调控知之甚少。 ASCL 1基因转录。这种知识差距反映了过去的技术挑战， 识别和操纵在距离细胞较远的地方发现的顺式调节元件（RE） 感兴趣的基因远程控制关键发育基因的RE是 利用先进的技术，可以询问和操纵 空间基因组在这里，我们将利用这些技术来获得急需的见解， 使用细胞培养和神经发育的体内模型进行ASCL 1的转录控制。 每种模型都有一个特定的优势，允许ASCL 1调节的独特方面， 发现了目的包括识别和测试控制ASCL 1的远程RE的功能 在小鼠（体内）和人类（体外）模型中神经元分化期间。成功在这些 目的是提供控制ASCL 1表达的功能性非编码调控序列。 这对于未来的项目识别信号复合物的分子组分是重要的 通过这些RE工作，以达到理解关键 谱系定义转录调节因子在发育和疾病过程中受到控制。