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Tissue biology studies of histone modification, nascent transcription, and post-transcription regulation

组蛋白修饰、新生转录和转录后调控的组织生物学研究

基本信息

批准号：
10746577
负责人：
JOHN T LIS
金额：
$ 57.07万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10746577
关键词：
Address Adult Affect Biological Models Biological Process Biology Cell Lineage Cell Maintenance Cell Separation Cell physiology Cells Chromatin Data Development Developmental Gene Disease Dissociation Drug Design Embryo Embryonic Development Enzymes Epigenetic Process Epithelium Future Gene Expression Regulation Gene Silencing Gene Targeting Genes Genetic Genetic Transcription Genomic approach Hair Hair follicle structure Heterochromatin Histone H3 Histones Homeostasis Impairment Investigation Knock-out Knockout Mice Knowledge Maps Mediating Messenger RNA Methodology Methods Methyltransferase Molecular Morphogenesis Mus Natural regeneration Normal tissue morphology Nuclear Pathology Pattern Physiological Polymerase Population Post-Transcriptional Regulation Productivity RNA RNA Polymerase II RNA Probes RNA Stability Regulation Repression Role Running Skin Stratification Therapeutic Uses Time Tissue Engineering Tissues Transcript Transcription Elongation Transcription Initiation Transferase Work cell type conditional knockout gene repression genome-wide histone methylation histone methyltransferase histone modification in vivo inducible Cre insight keratinocyte liver development mouse genetics mouse model novel pancreas development pharmacologic posttranscriptional promoter prototype recruit skin organogenesis tissue mapping tissue stem cells tool transcriptome sequencing wound healing

项目摘要

Abstract Basic cellular processes essential to mammalian tissue development and adult regeneration, are often controlled by gene expression regulation at the mRNA level. Total mRNA level for each gene depends on two mechanisms: active (or ‘nascent’) transcription and post-transcriptional RNA stability/degradation (e.g. turnover rates). Nascent transcription itself is regulated by multiple steps of recruiting histone-modifying enzymes and opening chromatin, RNA polymerase II (Pol II) initiation and pausing, and the release of Pol II into productive RNA elongation. Diverse mechanisms that regulate total mRNA level may be important in controlling distinct biological processes and pathologies, but this is poorly understood in vivo. Using skin as a model system we will map lineage-specific gene patterns of RNA Pol II activity and nascent transcription in specific cell-types within their natural tissue milieu in the absence of cell isolation. Furthermore, we will investigate changes in these nascent-transcription patterns along an adult tissue stem cell activation and differentiation path, using hair follicle as a lineage prototype. In addition, our work will help dissect relative contributions of active transcription vs post-transcriptional RNA turnover/stability to overall mRNA levels in specific cell types in vivo. Furthermore, we will determine how a known histone repressive mark (H3K9me3), poorly understood in mammalian tissues, acts on nascent transcription and RNA Pol II pausing in vivo. We will uncover for the first time the physiological role of the 3 main H3K9me3 histone methyl transferases in skin development and homeostasis. Finally, we will investigate how H3K9me3 acts on nascent transcription in vivo using our newly developed mouse genetics tools and methodologies. Our work will provide previously unavailable mechanistic insight into gene regulation in mammalian tissue biology using skin as a model system.

摘要哺乳动物组织发育和成体再生所必需的基本细胞过程是通常由mRNA水平的基因表达调控控制。每种的总mRNA水平基因依赖于两种机制：主动（或“起始”）转录和转录后 RNA稳定性/降解（例如周转率）。新生转录本身受招募组蛋白修饰酶和打开染色质的多个步骤，RNA聚合酶 II（Pol II）起始和暂停，以及Pol II释放到生产性RNA延伸中。多样化调节总mRNA水平的机制可能在控制不同的生物学过程中是重要的。过程和病理，但这在体内知之甚少。使用皮肤作为模型系统我们将绘制RNA Pol II活性和新生转录的谱系特异性基因模式，在没有细胞分离的情况下，在它们的天然组织环境中的特定细胞类型。此外，委员会认为，我们将研究沿着成人组织干细胞的这些起始转录模式的变化激活和分化途径，使用毛囊作为谱系原型。此外，我们的工作将有助于剖析活性转录与转录后RNA的相对贡献在体内特定细胞类型中的总mRNA水平的转换/稳定性。此外，我们将确定一个已知的组蛋白抑制标记（H3 K9 me 3），在哺乳动物中知之甚少，组织，作用于体内的新生转录和RNA Pol II暂停。我们将首次揭开 3种主要的H3 K9 me 3组蛋白甲基转移酶在皮肤中的生理作用发育和体内平衡。最后，我们将研究H3 K9 me 3如何作用于新生的使用我们新开发的小鼠遗传学工具和方法进行体内转录。我们这项工作将为哺乳动物基因调控提供以前无法获得的机制性见解。使用皮肤作为模型系统的组织生物学。