Deciphering enhancer regulation in stem cells

破译干细胞中的增强子调控

• 批准号: 10711332
• 负责人: Kaixiang Cao
• 金额: $ 40.25万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711332
• 关键词: Area; Cells; Chromatin; Development; Disease; Embryonic Development; Enhancers; Enzymes; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Health; Higher Order Chromatin Structure; Histones; Human; KDM1A gene; Knowledge; Laboratories; Malignant Neoplasms; Pathogenesis; Physiological Processes; Play; Pluripotent Stem Cells; Proteins; Reader; Regulation; Research; Role; Transcriptional Regulation; antagonist; developmental disease; histone demethylase; histone methyltransferase; human disease; insight; novel; pluripotency; pluripotency factor; recruit; self-renewal; stem cell differentiation; stem cell self renewal; stem cells

Project Summary The hallmark of pluripotent stem cells (PSCs) is their capability to self-renew and differentiate, which is governed by the core pluripotency circuitry consisting of pluripotency factors OCT4, SOX2, and NANOG. Enhancers are fundamental in regulating the spatial and temporal expression of pluripotency genes and lineage specific genes during cellular differentiation and embryogenesis. Enhancer-regulating epigenetic modifiers play critical roles in normal physiological processes and human pathogenesis. Epigenetic marks such as H3K4me1 and H3K27ac are widely believed to regulate the activity and higher-order chromatin structure of enhancers by directly remodeling local chromatin and/or recruiting reader proteins. However, recent discoveries of catalytic- independent functions of multiple histone modifiers suggest that these enzymes govern enhancers and stem cell differentiation via a non-catalytic manner. Despite the importance of epigenetic modifiers in mammalian development and human diseases, how they sustain stem cell identity and impact human health is poorly understood. I previously demonstrated that while enhancer activation does not require the catalytic activity of histone methyltransferase MLL4 in PSCs, it is regulated by the functional antagonism between MLL4 and histone demethylase LSD1. Using state-of-the-art unbiased approaches, my lab recently unveiled novel mechanisms underlying the role of enhancer-regulating epigenetic modifiers in PSCs, providing insight into elucidating gene regulation and cell fate transition. Here, I propose to build two research areas in my laboratory focused on enhancer-regulating epigenetic modifiers. The first research area will focus on identifying catalytic-independent functions of LSD1 in governing gene expression and cellular differentiation. The second research area will focus on determining how MLL4 and its interactors modulate enhancer activity and cell fate transition. I anticipate that accomplishing the proposed studies will reveal novel mechanisms underlying enhancer regulation, decipher how stem cell self-renewal and differentiation are governed, and pave the way for understanding the pathogenesis of diseases driven by enhancer malfunction.

项目摘要 多能干细胞（PSC）的标志是它们自我更新和分化的能力 由核心多能电路由多能因子Oct4，Sox2和Nanog组成。增强剂是 调节多能基因和谱系特定基因的空间和时间表达的基础 在细胞分化和胚胎发生过程中。增强剂调节的表观遗传修饰符在 正常的生理过程和人类发病机理。表观遗传标记，例如H3K4ME1和H3K27AC 人们普遍认为可以通过直接调节增强剂的活性和高阶染色质结构 重塑局部染色质和/或招募读取器蛋白。但是，最近发现的催化 多个组蛋白修饰剂的独立功能表明这些酶控制增强剂和干细胞 通过非催化方式分化。尽管表观遗传修饰剂在哺乳动物中很重要 发展和人类疾病，它们如何维持干细胞的身份和影响人类健康状况很差 理解。我先前证明，尽管增强子激活不需要 组蛋白甲基转移酶MLL4在PSC中，它受MLL4和组蛋白之间的功能拮抗作用调节 去甲基酶LSD1。我的实验室使用最新的公正方法，最近揭开了新的机制 在PSC中，增强子调节的表观遗传修饰剂的作用是阐明基因的洞察力 调节和细胞命运转变。在这里，我建议在我的实验室中建立两个研究领域 增强子调节的表观遗传修饰符。第一个研究领域将着重于识别独立于催化的 LSD1在控制基因表达和细胞分化中的功能。第二个研究领域将重点 在确定MLL4及其相互作用器如何调节增强子活性和细胞命运转变时。我预料到了 完成所提出的研究将揭示增强子调节的基础新机制，解密如何 干细胞自我更新和分化受到控制，并为理解的发病机理铺平了道路 增强剂故障驱动的疾病。