CAREER: Characterization of Epigenetic Factors and Their Regulatory Roles in Modulating Mitotic Fidelity

该奖项全部或部分根据2021年美国救援计划法案（公法117- 2）资助。细胞分裂是细胞增殖和生物体生长所需的重要过程。细胞分裂中的显著缺陷会导致不能存活的子细胞并损害生物体的生长。细胞分裂过程中更细微的缺陷会促进基因组的变化，从而促进细胞进化。细胞的遗传物质被组织成称为染色体的离散结构。当细胞分裂时，染色体被称为有丝分裂纺锤体的分子机器均等地分为两个新的子细胞。纺锤体和染色体之间的相互作用部分是由对组织遗传物质的蛋白质分子进行的修饰所控制的。然而，对于准确的染色体分选至关重要的不同修饰，以及控制这些修饰何时被放置或移除的调控过程，尚未完全理解。该项目将研究染色体和细胞分裂机制之间形成连接所必需的关键修饰。研究者将使用细胞和分子方法来修饰单个调节剂和相应的修饰。使用高分辨率显微镜，这项研究将通过实验测试细胞分裂过程中每种修饰的相关性，从而更好地了解染色体的调节以及更普遍的细胞分裂的基本过程。这项工作的更广泛影响包括研究本身的内在价值，因为所有真核细胞都可能利用待研究的过程。 其他活动包括努力增加STEM的多样性，高中生，本科生和研究生参与研究本身。 建议努力提高科学素养。 美国救援计划基金在她职业生涯的关键阶段为这位研究者提供了支持。有丝分裂染色体分离是细胞增殖和生物体生长所需的一个重要过程。在有丝分裂过程中，染色体被称为有丝分裂纺锤体的微管结构分离成两个子细胞。微管通过着丝粒附着在染色体上，着丝粒是一种蛋白质结构。着丝粒由CENPA（一种组蛋白H3变体）的沉积在表观遗传学上定义。与着丝粒染色质中组蛋白尾部的翻译后修饰一起，CENPA募集动粒形成所必需的核心蛋白。着丝粒两侧是组成性异染色质区域，称为近着丝粒。虽然着丝粒和近着丝粒异染色质的表观遗传调节与染色体分离的调节有关，但近着丝粒异染色质的表观遗传和分子成分影响动粒结构和功能的分子和机制基础仍不清楚。该项目将利用分子，细胞和成像方法来机械地定义有丝分裂错误校正和染色体分离的调节的着丝粒周围异染色质的表观遗传调制的作用。通过鉴定有丝分裂保真度的关键表观遗传调节剂并定义当相应的表观遗传修饰被破坏时有丝分裂受损的潜在机制，该项目将促进我们对着丝粒周围异染色质的生物学意义的理解，并更广泛地促进我们对细胞分裂基本过程的理解。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知识价值和更广泛的影响审查标准进行评估。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117- 2).Cell division is an essential process required for cellular proliferation and organismal growth. Dramatic defects in cell division can result in non-viable daughter cells and compromise organismal growth. More subtle defects during cell division promote changes in the genome that contribute to cellular evolution. The cell’s genetic material is organized into discrete structures known as chromosomes. When a cell divides the chromosomes are sorted equally into the two new daughter cells by a molecular machine called the mitotic spindle. The interactions between the spindle and chromosomes are governed, in part, by modifications made to the protein molecules that organize the genetic material. However, the distinct modifications that are critical for accurate chromosome sorting, and the regulatory processes that control when these modifications are placed or removed, are not completely understood. This project will investigate the key modifications that are necessary for the formation of connections between chromosomes and the cell division machinery. The investigator will use cell and molecular approaches to modify individual regulators and corresponding modifications. Using high resolution microscopy, this research will experimentally test the relevance of each modification in the cell division process, leading to a better understanding of both the regulation of chromosomes and, more generally, the fundamental process of cell division. The Broader Impacts of this work include the intrinsic merit of the research itself as all eukaryotic cells likely utilize the processes to be studied. Additional activities include efforts to increase the diversity in STEM, involvement of high school students, undergraduates, and graduate students in the research itself. Efforts to improve scientific literacy are proposed. American Rescue Plan funding provides support for this investigator at a critical stage in her career.Mitotic chromosome segregation is an essential process required for cellular proliferation and organismal growth. During mitosis, chromosomes are segregated into two daughter cells by a microtubule based structure known as the mitotic spindle. Microtubules attach to chromosomes via the kinetochore, a proteinaceous structure built upon the centromere. The centromere is defined epigenetically by the deposition of CENPA, a Histone H3 variant. Together with post-translational modifications of histone tails in centromeric chromatin, CENPA recruits the core proteins necessary for kinetochore formation. Flanking the centromere are regions of constitutive heterochromatin, termed the pericentromere. While epigenetic modulation of centromeric and pericentromeric heterochromatin has been implicated in the regulation of chromosome segregation, the molecular and mechanistic basis by which epigenetic and molecular constituents of pericentromeric heterochromatin impact kinetochore structure and function remain unclear. This project will utilize molecular, cellular, and imaging approaches to mechanistically define the role of epigenetic modulation of pericentromeric heterochromatin on the regulation of mitotic error correction and chromosome segregation. By identifying key epigenetic modulators of mitotic fidelity and defining the underlying mechanism by which mitosis is compromised when the corresponding epigenetic modifications are disrupted, this project will advance both our understanding of the biological significance of the pericentromeric heterochromatin and more broadly our understanding of the fundamental process of cell division.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.