Revealing the transcriptional and developmental mechanisms of interneuron identity

皮质GABA能中间神经元是神经回路的关键组成部分，并且它们的功能障碍已经被发现。 与神经发育疾病有关虽然中间神经元的多样性是没有争议的，但两者的程度 它们的异质性和驱动它的基因调控机制仍不清楚。的最新进展 单细胞RNA测序技术为这一问题提供了新的线索，能够预测新的 基于基因表达的中间神经元亚型。跨物种荟萃分析将提供关键的洞察力， 中间神经元多样性的保守机制。然而，跨学科整合仍然是一个重大挑战。 我假设中间神经元的身份是通过跨物种的统一分子过程来定义的。这个项目 旨在通过使用综合的跨物种方法来探索这些过程， 转录，表观遗传和发育机制，管理interneuron多样性。首先我得 显示小鼠中间神经元亚型可复制地表达与细胞间通讯相关的基因， 实现跨数据集的元分析。目标1的目标是使用改进的计算和系统发育 方法来定义跨物种的同源中间神经元亚型，并确定强大的基因靶点。第二、 单细胞甲基化测序数据的初步研究表明，它可以很容易地与 表达数据。在目标2中，我将使用机器学习方法从表观基因组和 表达数据并鉴定亚型特异性调控特征。第三，我已经证明了转录 可以相对于成体表达数据定量评估来自发育中神经元的分布。目标3 将使用时间推断方法的元分析聚合来实现跨数据集比较， 定义保守的发育基因程序。这些研究将揭示一个多维的肖像， 这是BRAIN Initiative的一个关键目标。 我还提出了一项广泛的培训计划，以支持我向独立过渡。CSHL提供了一个 优秀的研究环境，无与伦比的科学讨论机会，先进的技能 培训和职业发展。我组建了一支由合作者和导师组成的优秀团队， 帮助我实现我的目标。转录组荟萃分析专家Jesse Gillis博士和Josh Huang博士， 伽马氨基丁酸能中间神经元特性的专家，将是我的导师。任兵博士、亚当·西佩尔博士、郭平博士 冯博士、杰西卡·托尔库恩博士和迈克尔·格林伯格博士将是我的顾问团队的合作者和成员。 我相信我的研究将是最高水平的。我的培训还将涉及以下课程： 多组学数据整合和比较基因组学，我将继续我的专业发展， 出席国际会议，指导学生并参加CSHL的研讨会。统称 建议的学习和专业培训将确保我成功过渡到一个独立的职位， 我将在一所主要大学领导一个实验室，推进BRAIN Initiative的目标。

Cortical GABAergic interneurons are critical components of neural circuitry, and their dysfunction has been linked to neurodevelopmental diseases. Although the diversity of interneurons is not disputed, both the extent of their heterogeneity and the gene regulatory mechanisms that drive it remain unclear. Recent advances in single cell RNA-sequencing technology have shed new light on this issue, enabling the prediction of novel interneuron subtypes based on gene expression. Cross-species meta-analysis would provide key insight into conserved mechanisms of interneuron diversity. However, cross-study integration remains a major challenge. I hypothesize that interneuron identity is defined by unifying molecular processes across species. This project is designed to reveal these processes by using an integrative, cross-species approach to explore the transcriptional, epigenetic, and developmental mechanisms that govern interneuron diversity. First, I have shown that mouse interneuron subtypes replicably express genes associated with cell-cell communication, enabling cross-dataset meta-analysis. The goal of Aim 1 is to use improved computational and phylogenetic methods to define homologous interneuron subtypes across species and identify robust gene targets. Second, preliminary investigation of single cell methylome-sequencing data indicates that it can be readily aligned with expression data. In Aim 2 I will use machine learning methods to generate networks from epigenomic and expression data and identify subtype-specific regulatory features. Third, I have shown that transcriptional profiles from developing neurons can be quantitatively assessed with respect to adult expression data. Aim 3 will use meta-analytic aggregation of temporal inference methods to enable cross-dataset comparisons and define conserved developmental gene programs. These studies will reveal a multidimensional portrait of interneuron molecular identity and enable genetic access to these cell types, a key aim of the BRAIN Initiative. I also propose an extensive training plan that will support my transition to independence. CSHL provides an outstanding research environment, with unequaled opportunities for scientific discussion, advanced skills training and career development. I have assembled an exceptional team of collaborators and mentors who will help me to achieve my goals. Dr. Jesse Gillis, expert in transcriptome meta-analysis, and Dr. Josh Huang, expert in GABAergic interneuron identity, will be my mentors. Dr. Bing Ren, Dr. Adam Siepel, Dr. Guoping Feng, Dr. Jessica Tollkuhn and Dr. Michael Greenberg will be collaborators and members of my advisory committee, ensuring that my research will be of the highest caliber. My training will also involve coursework in multiomics data integration and comparative genomics, and I will continue my professional development by presenting at international conferences, mentoring students and attending workshops at CSHL. Together, the proposed studies and professional training will ensure my successful transition to an independent position at a major university where I will lead a lab that will advance the goals of the BRAIN Initiative.