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生物体根据经验改编其行为的能力。在细胞 级别，关于体验如何稳定改变行为的一个公认的观点是新的mRNA和蛋白质 综合发生，并且这种新状态在染色质，DNA和 决定转录状态的蛋白质。睡眠是在动物上发现的极其组成的驱动器 可能有助于这些过程的王国。我们假设其中一种进化构成了功能 睡眠是为了影响基因表达和染色质调节。有多种证据 支持睡眠对于转录调节和染色质稳定性很重要的想法，但迄今为止没有人 已直接比较了脊椎动物或大脑之间对睡眠损失的转录反应 同一物种中的其他组织。这很重要，因为确定组成机制是 比较整个进化时间所必需的。 所有对睡眠的OMICS研究的另一个关键局限性是单细胞水平缺乏分辨率。这是 重要的是，正如我们的初步研究所示，不同的细胞类型对睡眠损失的反应不同。 此外，单个单元格级缺乏分辨率可以使变化之间的映射对应关系 基因表达和染色质不准确的变化。单细胞转录组和 表观基因组分析是理解转录调节的途径。但是，单细胞 尚未应用方法来了解睡眠如何影响转录和染色质 规定。在最大化研究人员研究奖（MIRA）中，我们将利用最新的单细胞状态 基因组技术要首次定义常见的睡眠依赖性转录和表观遗传学 两种明显相关的脊椎动物物种之间的不同细胞类型的程序：小鼠和斑马鱼。 该建议利用了比较基因组学和进化，计算生物学以及 转录组和表观基因组技术在研究大脑和行为上的应用，我已经获得了训练 通过我的博士学位和博士后奖学金。目的是建立一个专注于的研究计划 了解不同物种的睡眠如何改变不同的转录和染色质可及性 细胞类型。在短期中 基因表达和染色质状态的调节，以及用于单细胞数据的公开软件 分析。从长远来看，这些研究将作为定义进化的功能研究的基础 睡眠可以调节基因表达和染色质结构的保守机制。