Tissue regeneration studies by controlled H3 K4/9/27me3 levels in adult mouse skin

通过控制成年小鼠皮肤中的 H3 K4/9/27me3 水平进行组织再生研究

基本信息

批准号：
10394721
负责人：
Tudorita Tumbar
金额：
$ 34.89万
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 2023-07-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394721
关键词：
Acetylation Address Adult Affect Antineoplastic Agents Basic Science Biological Models Biological Process Biology Cell Fate Control Cell division Cells Chemicals Clinical Clinical Trials Controlled Study DNA Modification Process Data Disease Drug Targeting Environment Environmental Risk Factor Epigenetic Process Epithelial Feedback Future Gene Expression Genetic Transcription Genetic study Genome Genomics Growth Hair Hair follicle structure Histone H3 Histones Homeostasis Human Inherited Link Malignant Neoplasms Messenger RNA Methylation Modernization Modification Molecular Mus Mutation Natural regeneration Normal tissue morphology Pathway interactions Pattern Pharmaceutical Preparations Process RNA RNA Degradation Reporting Role Signal Pathway Signal Transduction Skin Skin wound healing Sum Time Tissues Transcriptional Regulation Work base clinical application design embryonic stem cell epigenome experimental study genome sciences genome-wide global run on sequencing histone demethylase histone methylation histone modification in vivo mouse genetics regenerative therapy small molecule small molecule inhibitor stem cell fate stem cells success tissue regeneration tissue stem cells tool transcriptome transcriptome sequencing wound healing

项目摘要

Abstract Tissue regeneration therapy is a major endeavour in modern biology. Its success is dependent upon our ability to control cell fate decisions in adult tissue stem cells (SCs). Intrinsic genome plasticity and the crosstalk between SCs and their environment are important factors in cell fate decisions. Specialized epigenetic states, and particularly the genomic distribution and overall levels of covalent histone modifications (e.g. acetylation, methylation), are important for SC fates and for disease. Many small molecule inhibitors have been developed over the past decade to perturb histone modification levels, and some have already been implemented as cancer drugs in clinical trials. However, little has been done to manipulate levels of histone methylation in adult tissue SCs for possible control of tissue regeneration. Recently, we reported a global hypomethylation of histone H3 K4/9/27me3 that occurs at catagen in mouse skin, including in the quiescent hair follicle stem cells (HFSCs). Based on our preliminary data we hypothesize that perturbation of H3 K4/9/27me3 levels allows manipulation of tissue regeneration by engaging with signalling pathways essential in quiescent SCs. Here we use a combination of small molecule targeting and our newly developed mouse genetic tools to manipulate the levels of H3 K4/9/27me3 in adult mouse skin, and examine effects on tissue regeneration (e.g. hair follicle cycle and wound healing). We also begin to examine molecular mechanisms upstream and downstream of H3 K4/9/27me3 levels in HFSCs. In particular, we address for the first time in an adult mouse tissue in vivo the difference between steady state mRNA levels and nascent RNA levels and establish the direct link with histone methylation levels. Our work has implications for understanding the basic science of genome plasticity in quiescent tissue SCs and for examining the use of epigenetics-targeting drugs to skin and hair follicle regenerative therapies.

抽象的组织再生治疗是现代生物学的一项重大努力。它的成功取决于我们的能力控制成体组织干细胞（SC）的细胞命运决定。内在基因组可塑性和串扰 SC 与其环境之间的关系是细胞命运决定的重要因素。特殊的表观遗传状态，特别是共价组蛋白修饰的基因组分布和总体水平（例如乙酰化、甲基化），对于 SC 命运和疾病很重要。许多小分子抑制剂已被开发出来过去十年来扰乱组蛋白修饰水平，其中一些已经被实施为临床试验中的抗癌药物。然而，在控制成人组蛋白甲基化水平方面几乎没有采取任何措施。组织 SC 用于可能控制组织再生。最近，我们报告了全球低甲基化组蛋白 H3 K4/9/27me3 出现在小鼠皮肤的退行期，包括静止的毛囊干细胞中（HFSC）。根据我们的初步数据，我们假设 H3 K4/9/27me3 水平的扰动允许通过参与静止 SC 中必需的信号通路来操纵组织再生。在这里我们结合使用小分子靶向和我们新开发的小鼠遗传工具来操纵成年小鼠皮肤中 H3 K4/9/27me3 的水平，并检查对组织再生（例如毛囊）的影响周期和伤口愈合）。我们也开始研究H3上游和下游的分子机制 HFSC 中的 K4/9/27me3 水平。特别是，我们首次在成年小鼠体内组织中解决了稳态 mRNA 水平和新生 RNA 水平之间的差异，并建立与组蛋白的直接联系甲基化水平。我们的工作对于理解基因组可塑性的基础科学具有重要意义静止组织 SC 并用于检查表观遗传学靶向药物对皮肤和毛囊的使用再生疗法。