Molecular Regulation of Epigenetic Inheritance

智力优势：在真核生物中，DNA与组蛋白一起包装成一个高度复杂的结构，称为染色质。DNA和组蛋白的化学修饰在染色质结构和基因表达的控制中起着关键作用。这些修饰被称为“表观遗传标记”，可以忠实地遗传许多代。在DNA复制过程中，染色质在复制叉前拆卸，然后在叉后重新组装成其原始表观遗传状态。关于表观遗传标记，特别是组蛋白修饰如何遗传到新复制的染色质上的关键问题，仍然知之甚少。该项目的目标是了解表观遗传标记遗传的基本原理。裂变酵母（Schizosaccharomyces pombe）将用于解决这一重要的知识空白。裂变酵母是一种简单的，遗传上易于处理的模式生物，它包含了许多存在于高等真核生物中的表观遗传成分，因此最近成为表观遗传研究的首要模型。在裂变酵母中，组蛋白H3在赖氨酸9 （H3K9）处的甲基化在染色质中富集，这是染色质中高度浓缩和转录沉默的部分。异染色质的这种保守的表观遗传标志是稳定地代代遗传的，为理解真核生物表观遗传背后的机制提供了一个有价值的框架。在这个项目中，将使用包括遗传学、生物化学和细胞学在内的多种方法来确定参与DNA复制的蛋白质在H3K9甲基化遗传中的作用。这些发现将确定DNA复制和H3K9甲基化遗传之间的关键机制联系，并为这两个过程如何耦合提供重要见解。本研究将有助于理解表观遗传信息遗传的分子机制。更广泛的影响：在S. pombe中发现的表观遗传机制可能适用于多细胞真核生物。在植物和动物中，表观遗传标记的调控缺陷常常导致基因组不稳定和发育障碍。因此，该研究对农业、生态和经济具有重要意义。该项目将培养细胞生物学、遗传学和生物化学方面的博士后、研究生和本科生。PI将继续招收代表性不足的少数民族和女性学生参与研究。该项目还将作为PI在纽约大学教授的课程的教学资源，以及旨在鼓励K-12学生考虑从事科学职业的推广项目。

Intellectual Merit: In eukaryotes, DNA is packaged together with histone proteins into a highly complex structure called chromatin. Chemical modifications to DNA and histones play a key role in the control of chromatin structure and gene expression. These modifications, known as "epigenetic marks", can be faithfully inherited through many generations. During DNA replication, chromatin is disassembled ahead of the replication fork and then reassembled into its original epigenetic state behind the fork. Key questions on how epigenetic marks, particularly histone modifications, are inherited onto newly replicated chromatin, remain poorly understood. The goal of this project is to understand the fundamental principles underlying the inheritance of epigenetic marks. Fission yeast (Schizosaccharomyces pombe) will be used to address this important gap in knowledge. Fission yeast is a simple, genetically tractable model organism that contains many of the epigenetic components present in higher eukaryotes, and has thus recently emerged as a premier model for epigenetic study. In fission yeast, the methylation of histone H3 at lysine 9 (H3K9) is enriched in heterochromatin, the highly condensed and transcriptionally silent part of chromatin. This conserved epigenetic hallmark of heterochromatin is stably inherited from generation to generation, and provides a valuable framework for understanding the mechanisms behind epigenetic inheritance in eukaryotes. In this project, a combination of approaches, including genetics, biochemistry, and cytology, will be used to determine the role of proteins involved in DNA replication in the inheritance of H3K9 methylation. These findings will identify a key mechanistic link between DNA replication and the inheritance of H3K9 methylation, and provide important insights into how these two processes are coupled. This research will contribute to the understanding of the molecular mechanisms governing the inheritance of epigenetic information.Broader Impacts: The epigenetic mechanisms found in S. pombe will likely apply to multicellular eukaryotes. Defects in the regulation of epigenetic marks often result in genomic instability and developmental disorders in both plants and animals. This study thus has important implications for agriculture, ecology and economy. This project will train post-doc researchers, graduate students, and undergraduates in cell biology, genetics, and biochemistry. The PI will continue to recruit underrepresented minority and women students to participate in research. This project will also serve as a teaching resource for courses that the PI teaches at New York University and for an outreach program aimed at encouraging K-12 students to consider careers in science.