Regulatory mechanisms of cerebellar lineage development

小脑谱系发育的调节机制

基本信息

批准号：
10799998
负责人：
CHIN CHIANG
金额：
$ 55.48万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10799998
关键词：
Affect Ataxia Binding Binding Sites Brain CDK4 gene Cell Cycle Cell Cycle Progression Cell Lineage Cerebellar Diseases Cerebellum Clustered Regularly Interspaced Short Palindromic Repeats Complex Congenital cerebellar hypoplasia Data Development Disease Down-Regulation Embryo Enhancers Epigenetic Process Feedback Foundations Gene Expression Generations Genes Genetic Transcription Goals Histone Deacetylase Human Knowledge Learning Modeling Motor Neurons Nucleic Acid Regulatory Sequences Outcome Play Post-Translational Regulation Premature Infant Proliferating Proteins Repression Risk Factors Role Signal Transduction System Testing Time Transcription Repressor Zinc Fingers autism spectrum disorder cell type cognitive task genetic corepressor granule cell insulinoma associated 1 medulloblastoma motor behavior nervous system disorder novel postmitotic postnatal protein degradation sensory integration transcription factor

项目摘要

PROJECT SUMMARY Granule cells (GCs) constitute over 95% of the cerebellar volume. They receive and integrate sensory, motor, and non-sensorimotor signals to fine-tune motor behaviors and cognitive tasks. GCs are generated from transiently proliferating granule cell precursors (GCPs) over a long time extending from early embryonic period until first postnatal year in human. Accordingly, cerebellar hypoplasia is one of the most common brain complications in premature infants with poor developmental outcomes. We have very limited basic knowledge of how GC lineage is established. Our long term goals are to elucidate the regulatory mechanisms of GC lineage development, and to understand how different risk factors cause cerebellar hypoplasia. A master regulator of GCP development is the bHLH transcription factor Atoh1 that maintains the GCP fate through activation of its own expression. This autoregulatory feedback loop is further supported by a cell cycle regulator Ccnd1 that stabilizes Atoh1 protein from degradation. However, it remains unclear as to how Atoh1 and Ccnd1 expressions are terminated to enable timely progression from GCPs to GCs. Our preliminary data suggest that Sin3A, a component of histone deacetylase (Hdac)–containing transcriptional corepressor complex, is essential for GCP differentiation by epigenetically silencing Atoh1 expression. We have also identified Insm1, a zinc-finger transcription factor, as a potential partner of the Sin3A-Hdac complex that inhibits Atoh1 and Ccnd1 expression. Based on these and other preliminary observations, we propose the novel hypothesis that Atoh1 expression is dynamically controlled by H3K27 epigenetic signatures at the Atoh1 enhancer, with Insm1 as a key transcriptional repressor disrupting the Atoh1 autoregulatory loop and cell cycle progression, and enabling GC lineage differentiation. This hypothesis will be tested by determining (1) the epigenetic mechanism of Atoh1 expression and GC lineage differentiation, (2) Insm1 function and regulatory landscape during GC lineage development, and (3) the contribution of Insm1 in Atoh1 protein stability and GC lineage progression.

项目概要颗粒细胞 (GC) 占小脑体积的 95% 以上，它们接收并整合感觉、运动、 GC 产生用于微调运动行为和认知任务的非感觉运动信号。从胚胎早期开始，颗粒细胞前体细胞（GCP）在很长一段时间内短暂增殖直到人类出生后第一年，小脑发育不全是最常见的大脑发育不全之一。对于发育不良的早产儿的并发症，我们的基础知识非常有限。我们的长期目标是阐明 GC 谱系的调控机制。发育，并了解不同的危险因素如何导致小脑发育不全。 GCP 发育是 bHLH 转录因子 Atoh1，通过激活其维持 GCP 命运这种自动调节反馈循环得到细胞周期调节因子 Ccnd1 的进一步支持，该调节因子稳定 Atoh1 蛋白免于降解然而，Atoh1 和 Ccnd1 的表达方式仍不清楚。被终止以能够及时从 GCP 进展到 GC。我们的初步数据表明 Sin3A 是一种含有组蛋白脱乙酰酶 (Hdac) 的转录辅阻遏物复合物的成分，对于 GCP 至关重要通过表观遗传学沉默 Atoh1 表达来分化我们还鉴定了 Insm1，一种锌指。转录因子，作为 Sin3A-Hdac 复合物的潜在伴侣，抑制 Atoh1 和 Ccnd1 的表达。基于这些和其他初步观察，我们提出了 Atoh1 表达的新假设由 Atoh1 增强子上的 H3K27 表观遗传特征动态控制，以 Insm1 为关键转录抑制因子破坏 Atoh1 自动调节环和细胞周期进程，并促进 GC 该假设将通过确定 (1) Atoh1 的表观遗传机制来检验。表达和 GC 谱系分化，(2) GC 谱系期间 Insm1 功能和调控景观 (3) Insm1 在 Atoh1 蛋白稳定性和 GC 谱系进展中的贡献。