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

• 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
• 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

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.

摘要 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 以控制成体组织干细胞（SC）中的细胞命运决定。内在基因组可塑性和串扰 SC与其环境之间的相互作用是决定细胞命运的重要因素。专门的表观遗传状态， 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命运和疾病是重要的。许多小分子抑制剂已经被开发出来 在过去的十年中，干扰组蛋白修饰水平，有些已经被实施， 临床试验中的抗癌药物然而，几乎没有做过操纵成人组蛋白甲基化水平的研究。 组织SC用于可能控制组织再生。最近，我们报道了一个全球低甲基化的 组蛋白H3 K4/9/27 me 3，出现在小鼠皮肤的退行期，包括静止期毛囊干细胞中 （HFSC）。基于我们的初步数据，我们假设H3 K4/9/27 me 3水平的扰动允许 通过与静止SC中必不可少的信号传导通路接合来操纵组织再生。这里我们 使用小分子靶向和我们新开发的小鼠遗传工具的组合， H3 K4/9/27 me 3在成年小鼠皮肤中的水平，并检查对组织再生（例如毛囊）的影响 循环和伤口愈合）。我们也开始研究H3上游和下游的分子机制 HFSC中的K4/9/27 me 3水平。特别是，我们第一次在成年小鼠体内组织中讨论了 稳定状态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和检查表观遗传靶向药物对皮肤和毛囊的使用 再生疗法