Molecular Regulation of Epigenetic Inheritance

在真核生物中，DNA和组蛋白被包裹在一个叫做染色质的复杂结构中。组蛋白的化学修饰在染色质结构和基因表达的调控中起着至关重要的作用。这些修饰可以作为“表观遗传标记”，通过许多代忠实地传递，但遗传机制仍然知之甚少。该项目的目标是了解表观遗传标记遗传的基本原理。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、生态学和医学等多个领域具有重要意义。本项目将培养遗传学和生物化学方面的博士后、研究生和本科生。PI将招募未被充分代表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。在裂糖酵母（Schizosaccharomyces pombe）中，组蛋白H3赖氨酸9 （H3K9）甲基化富集于异染色质中，并稳定地代代遗传。RNA干扰机制（RNAi）在异染色质组装中也起着关键作用，因为小干扰RNA （sirna）促进H3K9甲基化。这一过程的核心是RITS （rna诱导的转录沉默）复合物，它与异染色质结合介导siRNA的产生和异染色质沉默。然而，RITS复合体如何促进复制叉后面的异染色质形成仍然未知。继DNA聚合酶epsilon的Dpb4亚基与Daf2相互作用促进异染色质沉默的新发现之后，该项目将(1)确定Daf2如何与异染色质转录物相互作用介导异染色质沉默，(2)确定Dpb4与Daf2之间的功能和物理关系，以及(3)确定Daf2在DNA复制过程中RITS复合体募集中的作用。该研究将提供DNA复制过程中RITS复合体如何在染色质上募集的见解，这对于理解异染色质表观遗传背后的机制具有重要意义。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

In eukaryotes, DNA and histone proteins are packed into a complex structure called chromatin. Chemical modifications of histones play a crucial role in the regulation of chromatin structure and gene expression. These modifications can serve as "epigenetic marks," which are faithfully transmitted through many generations, but the mechanism of inheritance remains poorly understood. The goal of this project is to understand the fundamental principles underlying the inheritance of epigenetic marks. Defects in the regulation of epigenetic marks often result in genomic instability and developmental disorders. Therefore, the study has important implications for several fields, such as agriculture, ecology and medicine. This project will train post-doctoral researchers, graduate students, and undergraduates in genetics and biochemistry. The PI will recruit underrepresented minority and women students to participate in the 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.In the fission yeast, Schizosaccharomyces pombe, histone H3 lysine 9 (H3K9) methylation is enriched in heterochromatin and is stably inherited from generation to generation. The RNA interference machinery (RNAi) also plays a pivotal role in heterochromatin assembly since small interfering RNAs (siRNAs) promote H3K9 methylation. Central to this process is the RITS (RNA-induced transcriptional silencing) complex, which associates with heterochromatin to mediate siRNA generation and heterochromatin silencing. However, how the RITS complex promotes heterochromatin formation behind the replication fork remains unknown. Following up a novel finding that the Dpb4 subunit of DNA polymerase epsilon interacts with Daf2 to promote heterochromatin silencing, the project will (1) determine how Daf2 interacts with heterochromatin transcripts to mediate heterochromatin silencing, (2) determine functional and physical relationship between Dpb4 and Daf2, and (3) determine the role of Daf2 in the recruitment of the RITS complex during DNA replication of peri-centromeric sequences. This study will provide insights into how the RITS complex is recruited on chromatin during DNA replication, which is important for understanding the mechanisms behind epigenetic inheritance of heterochromatin.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.