Molecular Regulation of Epigenetic Inheritance

在真核生物中，DNA和组蛋白被包装成一种称为染色质的复杂结构。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”，忠实地传递给许多代人，但遗传机制仍然知之甚少。这个项目的目标是了解表观遗传标记遗传的基本原则。表观遗传标记调控的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人员、研究生和本科生。PI将招募代表性不足的少数民族学生和女学生参加研究。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计划。在裂殖酵母裂殖酵母中，组蛋白H 3赖氨酸9（H 3 K 9）甲基化在异染色质中富集，并稳定地代代遗传。RNA干扰机制（RNAi）也在异染色质组装中起关键作用，因为小干扰RNA（siRNA）促进H3 K9甲基化。该过程的核心是RITS（RNA诱导的转录沉默）复合物，其与异染色质结合以介导siRNA产生和异染色质沉默。然而，RITS复合物如何促进复制叉后面的异染色质形成仍然未知。随着DNA聚合酶Dpb 4亚基与Daf 2相互作用以促进异染色质沉默的新发现，该项目将（1）确定Daf 2如何与异染色质转录物相互作用以介导异染色质沉默，（2）确定Dpb 4和Daf 2之间的功能和物理关系，和（3）确定Daf 2在着丝粒周围序列的DNA复制期间RITS复合物的募集中的作用。这项研究将深入了解DNA复制过程中RITS复合物是如何在染色质上被招募的，这对于理解异染色质表观遗传背后的机制非常重要。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

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.