Epigenetic Control of Nephron Progenitor Cell Lifespan

肾单位祖细胞寿命的表观遗传控制

• 批准号: 10915744
• 负责人: Samir S El-Dahr
• 金额: $ 10万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2024-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10915744
• 关键词: Age; Applications Grants; Atlases; Automobile Driving; Birth; Cell Differentiation process; Cells; Chromatin; Complex; Data; Development; Endowment; Enhancers; Epigenetic Process; Equilibrium; Exhibits; FOXP1 gene; Foundations; Gene Activation; Generations; Genes; Genetic; Genetic Transcription; Genetic study; Histones; Human; Kidney; Kidney Diseases; Knowledge; Longevity; Lysine; Maintenance; Mediating; Methylation; MicroRNAs; Mus; Natural regeneration; Nephrons; Organogenesis; Partner in relationship; Perinatal; Polycomb; Proteins; Protocols documentation; Publishing; RNA; Recommendation; Renal Mass; Repression; Role; Signal Transduction; TSC1 gene; Testing; Text; Time; Transcription Factor AP-1; Transgenic Mice; Translating; Work; activating transcription factor; cell type; demethylation; epigenetic regulation; fetal; glial cell-line derived neurotrophic factor; histone modification; multiple omics; nephrogenesis; nephron progenitor; novel; perinatal period; podocyte; prevent; programs; promoter; regenerative therapy; restraint; self-renewal; single cell analysis; stem cells; transcription factor

A significant barrier to progress in the renal regeneration field is insufficient knowledge surrounding the mechanisms driving cessation of nephrogenesis. Recent genetic and epigenetic evidence demonstrated that the lifespan of nephron progenitor cells (NPCs) is not fixed. Our published and preliminary data indicate that the perinatal period in mice is characterized by remarkable changes in the single-cell chromatin landscape that tip the balance of NPC self-renewal and differentiation. The principal aim of this one-year Bridge R56 grant proposal is to generate the preliminary data requested by the Review Panel supporting our hypothesis that chromatin/histone bivalency, established through the balance of histone H3K27 methylation/demethylation, maintains the NPC lifespan by restraining chromatin accessibility to pro-differentiation transcription factors. In Aim 1A, we will generate NPC-specific Kdm6bnull mice to test the hypothesis that inhibiting H3K27 demethylation of developmental enhancers will delay the timing of cessation of nephrogenesis and enhance nephron endowment. Aim 1B will generate NPC-specific activating transcription factor (ATF4)-transgenic mice to test the hypothesis that ATF4 is sufficient to drive the cessation of nephrogenesis. We discovered differential enrichment of ATF4 motif activity in perinatal NPCs by single-cell analysis. Interestingly, ATF4 motifs are enriched in bivalent promoters, supporting the overall premise that chromatin bivalency controls NPC lifespan. Collectively, the results of these studies will form a strong basis for the competitive renewal application, which will delve into the chromatin-based mechanisms of cessation of nephrogenesis. Successful completion of this project will have broad impacts on defining the rules of epigenetic control of nephron progenitor maintenance. This knowledge may be translated to optimizing nephron regeneration and understanding epigenetic programming of renal disease.

肾再生领域进展的一个重大障碍是对驱动肾发生停止的机制了解不足。最近的遗传和表观遗传证据表明，肾单位祖细胞（NPC）的寿命并不固定。我们发表的初步数据表明，小鼠围产期的特点是单细胞染色质景观发生显着变化，从而打破了 NPC 自我更新和分化的平衡。这项为期一年的 Bridge R56 拨款提案的主要目的是生成审查小组要求的初步数据，支持我们的假设，即通过组蛋白 H3K27 甲基化/去甲基化的平衡建立的染色质/组蛋白二价性，通过抑制染色质来维持 NPC 寿命促分化转录因子的可及性。在目标 1A 中，我们将生成 NPC 特异性 Kdm6bnull 小鼠，以测试抑制发育增强子的 H3K27 去甲基化将延迟肾发生停止时间并增强肾单位禀赋的假设。目标 1B 将产生 NPC 特异性激活转录因子 (ATF4) 转基因小鼠，以测试 ATF4 足以驱动肾发生停止的假设。我们通过单细胞分析发现围产期 NPC 中 ATF4 基序活性的差异富集。有趣的是，ATF4 基序富含二价启动子，支持染色质二价控制 NPC 寿命的总体前提。总的来说，这些研究的结果将为竞争性更新应用奠定坚实的基础，该应用将深入研究基于染色质的肾发生停止机制。 该项目的成功完成将对定义肾单位祖细胞维持的表观遗传控制规则产生广泛影响。这些知识可以转化为优化肾单位再生和理解肾脏疾病的表观遗传编程。