Deciphering enhancer regulation in stem cells

项目摘要 多能干细胞的标志是它们自我更新和分化的能力，这是由 由多能因子OCT4、SOX2和NANOG组成的核心多能电路。增强剂有 调节多能性基因和谱系特异性基因的时空表达的基础 在细胞分化和胚胎发育过程中。增强子调控的表观遗传修饰物在 正常的生理过程和人类的发病机制。H3K4me1和H3K27ac等表观遗传标记 被广泛认为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/或招募阅读器蛋白。然而，最近对催化的发现- 多个组蛋白修饰物的独立功能表明这些酶控制增强剂和干细胞 通过非催化方式进行分化。尽管表观遗传修饰物在哺乳动物中的重要性 关于发展和人类疾病，它们如何维持干细胞特性和影响人类健康的情况很差 明白了。我之前已经证明，虽然增强子的激活并不需要 组蛋白甲基转移酶MLL4在PSCs中的表达，受MLL4和组蛋白功能拮抗的调节 去甲基酶LSD1。使用最先进的无偏见方法，我的实验室最近推出了新的机制 PSCs中增强子调节表观遗传修饰物的作用，为阐明基因提供了洞察力 调控与细胞命运转换。在这里，我建议在我的实验室中建立两个研究区，重点是 增强子调控的表观遗传修饰物。第一个研究领域将集中在识别不依赖于催化剂的 LSD1在调控基因表达和细胞分化中的作用。第二个研究领域将集中在 关于确定MLL4及其相互作用因子如何调节增强子活性和细胞命运转变。我预料到了 完成拟议的研究将揭示潜在的增强子调控的新机制，破译如何 干细胞的自我更新和分化被调控，并为了解其发病机制铺平了道路。 由增强子故障引起的疾病。

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.