Chromatin architectural protein CTCF and regulation of skin development and tumorigenesis

染色质结构蛋白 CTCF 与皮肤发育和肿瘤发生的调节

基本信息

批准号：
9910061
负责人：
VLADIMIR A BOTCHKAREV
金额：
$ 50.31万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910061
关键词：
3-Dimensional Ablation Address Animal Genetics Animal Model Antineoplastic Agents Architecture Area Autoimmunity Biology CCCTC-binding factor Cell Lineage Cell Nucleus Cells Chromatin Chronic DNA Data Development Distal Enhancer Elements Enhancers Enzymes Epidermis Epigenetic Process Epithelial Epithelial Cells Epithelium Formaldehyde Gene Activation Gene Expression Gene Expression Regulation Gene Order Gene Silencing Genes Genetic Genetic Enhancer Element Genetic Transcription Genome Goals Hair Hair follicle structure Higher Order Chromatin Structure Histones Homeostasis Human Impairment Knowledge Link Maintenance Malignant Neoplasms Mediating Modification Mus Mutate Neoplastic Cell Transformation Neurons Oncogene Activation Oncogenes Pathologic Pattern Phenotype Play Polycomb Population Proteins Quality of life Regulation Regulatory Element Research Role Signal Transduction Skin Skin Cancer Structure Techniques Testing Therapeutic Intervention Tumor Suppressor Genes Tumor Suppressor Proteins Untranslated RNA WNT Signaling Pathway Zinc Fingers base carcinogenesis chromatin remodeling chromosome conformation capture crosslink epigenetic drug epithelial stem cell epithelial wound histone modification inhibitor/antagonist keratinocyte member neoplastic cell novel postnatal programs promoter skin barrier skin disorder skin organogenesis skin regeneration stem cell differentiation stem cells tissue regeneration transcription factor tumor tumorigenesis

项目摘要

PROJECT SUMMARY The long-term goal of this project is to understand how epithelial stem cells in the skin establish distinct patterns of gene activation and silencing during their differentiation into specialized cell lineages and how these genetic programs are re-organized during skin regeneration and tumorigenesis. It is now widely accepted that in addition to signaling/transcription factor-mediated mechanisms, lineage- specific gene expression programs are also regulated epigenetically, i.e., via covalent DNA/histone modifications, as well as via spatial arrangements of the genes and their enhancer elements in the nucleus. Enhancer-promoter interactions serve as key determinants providing functional and structural frameworks for cell-specific transcription controlled by lineage-specific transcription factors. However, enhancer-promoter regulatory networks are substantially re-organized during cell transition towards malignancy, which include an aberrant exposure of gene promoters to inappropriate regulatory elements resulting in activation of pro- oncogenes, as well as in silencing of the tumor suppressor genes. CCCTC-binding factor (CTCF) serves as one of the core architectural proteins that plays a key role in the control the establishment and maintenance of enhancer/promoter interactions. CTCF gene is frequently mutated in cancers, and abrogation of its tumor-suppressor activity contributes to cancer development and progression. Our preliminary data demonstrate that CTCF is expressed in both mouse and human epidermis, while Krt14-driven Ctcf genetic ablation results in severe alterations in skin development, epidermal barrier maintenance, and tumorigenesis. In this multi-PI proposal, we will test a hypothesis that CTCF serves as critical determinant that control the establishment and maintenance of the enhancer-promoter regulatory networks in skin epithelial stem cells and their progenies during development and postnatal homeostasis, while alterations in such networks result in skin tumorigenesis. We will address this hypothesis via two Specific Aims: 1. Define the roles of CTCF in the establishment and maintenance of lineage-specific higher-order chromatin structure, enhancer-promoter regulatory networks and gene expression in distinct populations of skin epithelial cells during development and hair cycle-associated skin regeneration. 2. Delineate the roles for Ctcf in regulation of gene expression, 3D chromatin organization and enhancer-promoter interactions in the skin epithelial cells during tumorigenesis. This project will have a fundamental impact on our current knowledge of epigenetic mechanisms that regulate genome reorganization in stem cells during their differentiation and tumorigenesis and will promote the progress towards the development of novel epigenetic drugs as a new paradigm for treatment of skin disorders.

项目概要该项目的长期目标是了解皮肤中的上皮干细胞如何建立独特的基因激活和沉默在分化为特化细胞谱系过程中的模式以及这些模式如何遗传程序在皮肤再生和肿瘤发生过程中被重新组织。现在人们普遍认为，除了信号/转录因子介导的机制之外，谱系- 特定的基因表达程序也受到表观遗传学的调节，即通过共价 DNA/组蛋白修饰，以及通过基因及其增强子元件在细胞核中的空间排列。增强子-启动子相互作用是提供功能和结构框架的关键决定因素用于由谱系特异性转录因子控制的细胞特异性转录。然而，增强子-启动子在细胞向恶性肿瘤转变过程中，调控网络发生了实质性的重组，其中包括基因启动子异常暴露于不适当的调控元件，导致前体激活癌基因，以及抑癌基因的沉默。 CCCTC 结合因子 (CTCF) 作为核心结构蛋白之一，在控制增强子/启动子相互作用的建立和维持。 CTCF基因频繁突变在癌症中，其肿瘤抑制活性的消除有助于癌症的发生和进展。我们的初步数据表明 CTCF 在小鼠和人类表皮中都有表达，而 Krt14驱动的Ctcf基因消融导致皮肤发育、表皮屏障的严重改变维持和肿瘤发生。在这个多 PI 提案中，我们将测试 CTCF 作为关键的假设控制增强子-启动子调控网络的建立和维持的决定因素皮肤上皮干细胞及其后代在发育和产后稳态过程中的变化这种网络会导致皮肤肿瘤发生。我们将通过两个具体目标来解决这个假设： 1. 明确CTCF在建立和维持谱系特定高阶中的作用染色质结构、增强子-启动子调控网络和不同基因表达发育和毛发周期相关的皮肤再生过程中的皮肤上皮细胞群。 2. 描述 Ctcf 在基因表达、3D 染色质组织和调控中的作用肿瘤发生过程中皮肤上皮细胞中增强子-启动子的相互作用。该项目将对我们目前对表观遗传机制的了解产生根本性影响在干细胞分化和肿瘤发生过程中调节基因组重组，并促进开发新型表观遗传药物作为治疗皮肤病的新范例的进展。