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，这是由细胞周期调控的。 通过由多能性因子OCT 4、SOX 2和NANOG组成的核心多能性回路。增强子是 在调节多能性基因和谱系特异性基因的空间和时间表达中起基础作用 在细胞分化和胚胎发生过程中。增强子调节表观遗传修饰剂在 正常生理过程和人体发病机制。表观遗传标记，如H3 K4 me 1和H3 K27 ac 被广泛认为通过直接调节增强子的活性和高级染色质结构 重塑局部染色质和/或募集阅读蛋白。然而，最近发现的催化剂- 多种组蛋白修饰剂的独立功能表明这些酶控制增强子和干细胞 通过非催化方式进行分化。尽管表观遗传修饰在哺乳动物中的重要性 发展和人类疾病，他们如何维持干细胞身份和影响人类健康是很差的 明白我以前证明，虽然增强子的激活不需要催化活性， 组蛋白甲基转移酶MLL 4在PSC中，它通过MLL 4和组蛋白之间的功能性拮抗作用来调节 脱甲基酶LSD 1。利用最先进的无偏方法，我的实验室最近公布了新的机制， 增强子调节表观遗传修饰剂在PSC中的作用，为阐明基因 调节和细胞命运转变。在这里，我建议在我的实验室建立两个研究领域， 增强子调节表观遗传修饰剂。第一个研究领域将集中在确定催化剂不依赖性 LSD 1在基因表达和细胞分化中的作用。第二个研究领域将重点 确定MLL 4及其相互作用物如何调节增强子活性和细胞命运转变。我预计 完成这些研究将揭示增强子调控的新机制， 干细胞的自我更新和分化受到控制，并为了解干细胞的发病机制铺平了道路。 由增强子功能障碍引起的疾病