Transposable elements in the keratinocyte genome and their regulation during skin development and epidermal differentiation

角质形成细胞基因组中的转座元件及其在皮肤发育和表皮分化过程中的调节

• 批准号: 10560618
• 负责人: VLADIMIR A BOTCHKAREV
• 金额: $ 48.89万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-16 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10560618
• 关键词: Ablation; Address; Aging; Animal Genetics; Animal Model; Area; Autoimmune Diseases; Biology; Candidate Disease Gene; Cell Differentiation process; Cells; Chromatin; Chromatin Remodeling Factor; Clinic; Code; Collaborations; Complex; DNA; DNA Methylation; DNA Methylation Regulation; DNA Modification Methylases; DNA Transposable Elements; Data; Data Correlations; Development; Disease Management; Distal Enhancer Elements; Double-Stranded RNA; Endogenous Retroviruses; Enhancers; Epidermis; Epigenetic Process; Epithelium; Equilibrium; Exhibits; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; HELLS gene; Heterochromatin; Histones; Homeostasis; Human; Human Genome; Hyperplasia; Immune response; Immunology; Inflammatory; Inflammatory Response; Innate Immune Response; Laboratories; Long Interspersed Elements; Lupus Erythematosus; Maintenance; Malignant Neoplasms; Maps; Mediating; Methylation; Minor; Mus; Mutant Strains Mice; Nature; Nucleosomes; Output; Pathologic; Patients; Pattern; Physiological; Play; Population; Prevention; Proteins; Psoriasis; Regulation; Research; Role; Signal Transduction; Site; Skin; Structure; Testing; Transcriptional Silencer Elements; Translations; UV Radiation Exposure; Untranslated RNA; autoimmune pathogenesis; carcinogenesis; chromatin remodeling; derepression; exhaust; histone methyltransferase; histone modification; insight; keratinocyte; keratinocyte differentiation; member; mouse genome; novel; novel therapeutic intervention; postnatal; premature; prevent; progenitor; programs; promoter; skin organogenesis; stem cells; tissue regeneration; transcription factor

PROJECT SUMMARY In addition to signaling/transcription factor-dependent regulatory mechanisms, lineage-specific gene expression programs in stem cells and their progenies are also regulated epigenetically, i.e., via regulation of covalent DNA/histone modifications and higher-order chromatin remodeling. Epigenetic regulatory machinery maintain the progenitor population and epithelial identity in epidermal keratinocytes, as well as inhibit premature activation of terminal differentiation-associated genes and balance their transcription in differentiating cells. Transposable elements (TEs) constitute a large portion (44%-55%) of the entire mouse or human genomes. Most TEs are transcriptionally inactive under physiological conditions, while their inappropriate activation has been implicated in pathogenesis of autoimmune disorders and carcinogenesis. In keratinocytes, UV exposure activates transcription of various endogenous retroviral sequences which are closely related to the sequences activated in lupus erythematosus patients. Furthermore, increasing evidence of data suggest an involvement of endogenous TEs in the development of pro-inflammatory skin conditions, such as psoriasis. However, there is a number of critical questions that this project seeks to investigate, remain unclear: 1) Which TEs are expressed in normal keratinocytes during skin development, postnatal homeostasis and terminal differentiation, 2) Which mechanisms regulate TE silencing in keratinocytes, and 3) When TE silencing is compromised, how are keratinocyte differentiation and epidermal inflammatory response impacted? In this Multi-PI proposal, we will address the hypothesis that distinct classes of TEs differentially contribute to the control of gene expression in epidermal keratinocytes, mediated by epigenetic regulators Lsh and Setdb1 that serve as critical determinants mediating the TE silencing and preventing pro-inflammatory responses in the epidermis. This hypothesis will be addressed via three Specific Aims: Aim 1. Define the landscape of transposable element expression in normal mouse and human keratinocytes during skin development, postnatal homeostasis and terminal differentiation. Aim 2. Define the roles for Lsh and Setdb1 in the control of transposable element silencing in keratinocytes. Aim 3. Define the impact and mechanisms associated with the transposable element activation in keratinocytes on epidermal inflammatory response. The generated outputs from this application will provide novel insights into fundamental mechanisms underlying keratinocyte differentiation in normal mouse and human skin, as well as will promote the development of novel paradigms for management of disorders of epidermal differentiation and inflammatory responses in humans via modulation of TE activities.

项目概要 除了信号/转录因子依赖性调节机制外，谱系特异性基因 干细胞及其后代中的表达程序也受到表观遗传的调节，即通过调节 共价 DNA/组蛋白修饰和高阶染色质重塑。表观遗传调控机制 维持表皮角质形成细胞中的祖细胞群和上皮身份，并抑制早熟 激活终末分化相关基因并平衡其在分化细胞中的转录。 转座元件 (TE) 构成整个小鼠或人类的很大一部分 (44%-55%) 基因组。大多数 TE 在生理条件下转录不活跃，而它们的不适当的 激活与自身免疫性疾病和癌发生的发病机制有关。在角质形成细胞中， 紫外线照射激活各种内源性逆转录病毒序列的转录，这些序列与 红斑狼疮患者中激活的序列。此外，越来越多的数据证据表明 内源性 TE 参与促炎性皮肤病（例如牛皮癣）的发展。 然而，该项目试图调查的一些关键问题仍不清楚： 1) 哪些 TE 在皮肤发育、产后稳态和正常角质形成细胞中表达 终末分化，2) 哪些机制调节角质形成细胞中的 TE 沉默，以及 3) TE 沉默何时发生 受到损害，角质形成细胞分化和表皮炎症反应如何受到影响？ 在这个多 PI 提案中，我们将提出这样一个假设：不同类别的 TE 的贡献存在差异 由表观遗传调节因子 Lsh 和 Setdb1 介导的表皮角质形成细胞基因表达的控制 作为介导 TE 沉默和预防促炎症反应的关键决定因素 表皮。这一假设将通过三个具体目标来解决： 目标 1. 定义正常小鼠和人类中转座元件表达的情况 皮肤发育、产后稳态和终末分化过程中的角质形成细胞。 目标 2. 定义 Lsh 和 Setdb1 在控制转座元件沉默中的作用 角质形成细胞。 目标 3. 定义与转座元件激活相关的影响和机制 角质形成细胞对表皮炎症反应的影响。 该应用程序生成的输出将为基本机制提供新颖的见解 正常小鼠和人类皮肤中潜在的角质形成细胞分化，并将促进发育 治疗表皮分化和炎症反应疾病的新范例 人类通过调节 TE 活动。