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.

项目摘要颗粒细胞（GC）占小脑体积的95％以上。他们接收并集成了感觉，电机，和非传感器信号，以微调运动行为和认知任务。 GC是由从早期胚胎时期延伸的长期延伸，瞬时增殖的颗粒细胞前体（GCP）直到人类的第一年。根据小脑发育不全是最常见的大脑之一发育效果不佳的早产儿的并发症。我们的基础知识非常有限 GC谱系的建立方式。我们的长期目标是阐明GC血统的调节机制发展，并了解不同的风险因素如何引起小脑发育不全。主管 GCP的开发是BHLH转录因子ATOH1，它通过激活其维持GCP命运自己的表达。这种自动调节反馈回路得到了细胞周期调节器CCND1的进一步支持从降解中稳定ATOH1蛋白。但是，尚不清楚ATOH1和CCND1表达式如何被终止以使及时从GCP到GCS的进展。我们的初步数据表明SIN3A，一个组蛋白脱乙酰基酶（HDAC）的成分 - 含有转录的核心配合物，对于GCP至关重要通过表观遗传沉默的ATOH1表达通过分化。我们还确定了INSM1，锌指转录因子，是抑制ATOH1和CCND1表达的SIN3A-HDAC复合物的潜在合作伙伴。基于这些和其他初步观察，我们提出了一个新的假设，即ATOH1表达是由ATOH1增强剂的H3K27表观遗传签名动态控制，并以INSM1为钥匙转录表示破坏ATOH1自动调节环和细胞周期进程，并启用GC 谱系分化。该假设将通过确定（1）ATOH1的表观遗传机理进行检验 GC谱系期间的表达和GC谱系分化，（2）INSM1功能和调节景观开发和（3）INSM1在ATOH1蛋白稳定性和GC谱系进程中的贡献。