The role of sleep on chromatin and transcriptional regulation across vertebrate evolution.

睡眠对脊椎动物进化过程中染色质和转录调控的作用。

• 批准号: 10707482
• 负责人: Lucia Peixoto
• 金额: $ 38.25万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10707482
• 关键词: Animals; Architecture; Atlases; Award; Behavior; Brain; Cells; Chromatin; Complex; Computational Biology; Computer software; DNA; Data Analyses; Distant; Doctor of Philosophy; Epigenetic Process; Evolution; Fellowship; Gene Expression; Gene Expression Regulation; Genetic Transcription; Genomics; Goals; Longitudinal Studies; Maps; Messenger RNA; Mus; Organism; Postdoctoral Fellow; Process; Protein Biosynthesis; Proteins; Regulation; Research; Research Personnel; Resolution; Role; Sleep; Sleep Deprivation; Technology; Time; Tissues; Training; Transcriptional Regulation; Zebrafish; behavior change; cell type; comparative genomics; epigenomics; experience; programs; response; transcriptomics

A key aspect of survival is an organism’ ability to adapt their behavior based on experience. At the cellular level, a well-established view of how experience can stably change behavior is that new mRNA and protein synthesis occurs, and that this new state becomes stably encoded in the chromatin, the complex of DNA and proteins that determines transcriptional state. Sleep is an extremely conserved drive found across the animal kingdom that may facilitate these processes. We hypothesize that one of the evolutionary conserved functions of sleep is to influence gene expression and chromatin regulation. There are multiple lines of evidence that support the idea that sleep is important for transcriptional regulation and chromatin stability, but to date no one has directly compared transcriptional responses to sleep loss across vertebrate species or between brain and other tissues within the same species. This is important because to determine conserved mechanisms it is necessary to compare across evolutionary time. Another key limitation of all omics studies of sleep is the lack of resolution at the single-cell level. This is important because, as show in our preliminary studies, different cell types respond differently to sleep loss. In addition, the lack of resolution at the single cell-level can make mapping correspondence between changes in gene expression and changes in chromatin inaccurate. The application of single-cell transcriptomic and epigenomic analysis is a promising avenue to understand transcriptional regulation. However, single-cell approaches have not yet been applied to understand how sleep influences transcription and chromatin regulation. In this Maximizing Investigators Research Award (MIRA) we will utilize state of the art single-cell genomic technology to define, for the first time, common sleep-dependent transcriptional and epigenetic programs across different cell-types between two distantly related vertebrate species: Mouse and Zebrafish. This proposal leverages expertise in comparative genomics and evolution, computational biology and the application of transcriptomic and epigenomic technology to study brain and behavior, training I have acquired throughout my PhD and post-doctoral fellowship. The goal is to establish a program of research focused on understanding how sleep across different species can alter transcription and chromatin accessibility in different cell-types. In the short-term this proposal will produce a comprehensive cell atlas of sleep-dependent regulation of gene expression and chromatin states, as well as publicly available software for single-cell data analysis. In the long-term these studies will serve as the basis for functional studies to define evolutionary conserved mechanisms by which sleep can modulate gene expression and chromatin architecture.

生存的一个关键方面是有机体根据经验调整其行为的能力。在细胞 水平，经验如何稳定地改变行为的一个公认观点是，新的mRNA和蛋白质 合成发生，并且这种新的状态在染色质中稳定编码，染色质是DNA和 决定转录状态的蛋白质。睡眠是一种在动物身上发现的极其保守的驱动力 王国，可以促进这些进程。我们假设进化保守功能之一 影响基因表达和染色质调节。有很多证据表明 支持睡眠对转录调节和染色质稳定性很重要的观点，但到目前为止，还没有人 直接比较了脊椎动物物种之间或大脑和大脑之间对睡眠不足的转录反应。 同一物种内的其他组织。这一点很重要，因为要确定保守的机制， 在进化过程中进行比较是必要的。 所有睡眠组学研究的另一个关键限制是缺乏单细胞水平的分辨率。这是 这一点很重要，因为正如我们初步研究所示，不同类型的细胞对睡眠不足的反应是不同的。在 此外，在单个单元格级别缺乏分辨率可能会使 基因表达和染色质变化不准确。单细胞转录组学和 表观基因组分析是理解转录调控的一个有希望的途径。然而，单细胞 目前还没有方法来了解睡眠如何影响转录和染色质 调控在这个最大化研究者研究奖（MIRA）中，我们将利用最先进的单细胞 基因组技术首次定义了常见的睡眠依赖性转录和表观遗传 在两个远亲脊椎动物物种之间的不同细胞类型的程序：小鼠和斑马鱼。 该提案利用了比较基因组学和进化、计算生物学和生物学方面的专业知识， 应用转录组学和表观基因组学技术来研究大脑和行为， 在我的博士和博士后奖学金中。目标是建立一个研究计划， 了解不同物种的睡眠如何改变不同物种的转录和染色质可及性。 细胞类型。在短期内，这一建议将产生一个全面的细胞图谱， 基因表达和染色质状态的调控，以及用于单细胞数据的公开可用软件 分析.从长远来看，这些研究将作为功能研究的基础， 睡眠可以调节基因表达和染色质结构的保守机制。