Mechanisms of chromatin and transcriptional regulation

组蛋白翻译后修饰(PTM)，染色质重塑酶，DNA 甲基化和组蛋白伴侣蛋白在组织和控制 我们的基因组。重要的是，负责的蛋白质或酶的破坏或突变 因为染色质的调节是许多人类疾病的基础，最明显的是癌症。 我们的长期目标是阐明染色质调节的分子基础 并定义这一规定如何对人类生物学和疾病做出贡献。我们的实验室有 带头追求这一目标，取得了开创性的发现，解释了 染色质修饰机制“写”和“读”组蛋白PTM以及组蛋白如何 PTMS在DNA转录、DNA复制、DNA修复和DNA维持中发挥作用 甲基化。然而，尽管取得了相当大的进展，但仍有许多至关重要的知识 差距。例如，组蛋白PTMS在多大程度上发挥作用在很大程度上是未知的。 组合方式。同样，我们也不完全了解 染色质中多种不同阅读域对组蛋白PTMS的识别作用 我们也不完全了解成对的阅读器结构域是如何结合的 核小体以多价方式存在。最后，我们不知道新的功能 确定了组蛋白PTM，例如赖氨酸巴豆化。有了这个Mira奖，我们的实验室将 通过回答三个最重要的基本问题来弥合这些知识差距 染色质生物学：1)组蛋白修饰酶和伴侣蛋白如何调节 转录，细胞周期，并保持染色质的完整性？2)最近怎么样 已发现的组蛋白PTM，如巴豆化有助于基因调控？3) 组蛋白PTM在多大程度上协同调节下游功能 染色质？ 好了！

Histone post-translational modifications (PTMs), chromatin-remodeling enzymes, DNA methylation, and histone chaperones play critical roles in the organization and control of our genomes. Importantly, disruption or mutation of the proteins or enzymes responsible for chromatin regulation underlies a number of human diseases, most notably cancer. Our long-term goal is to elucidate the molecular underpinnings of chromatin regulation and define how this regulation contributes to human biology and disease. Our lab has spearheaded the pursuit of this goal, making seminal discoveries that explain how the chromatin-modifying machinery “writes” and “reads” histone PTMs and how histone PTMs function in transcription, DNA replication, DNA repair, and maintenance of DNA methylation. Yet, despite considerable progress, there remain many crucial knowledge gaps. For example, it is largely unknown the extent to which histone PTMs function in a combinatorial manner. Similarly, we do not fully understand the biochemical basis for recognition of histone PTMs by the many different reader domains in chromatin- associated proteins nor do we fully understand how paired reader domains bind nucleosomes in a multivalent manner. Finally, we do not know the functions of newly identified histone PTMs, e.g., lysine crotonylation. With this MIRA award, our lab will close these knowledge gaps by answering three of the foremost fundamental questions in chromatin biology: 1) How do histone-modifying enzymes and chaperones regulate transcription, the cell cycle, and maintain chromatin integrity? 2) How do recently discovered histone PTMs such as crotonylation contribute to gene regulation? 3) To what extent do histone PTMs collaborate to regulate downstream functions in chromatin? !