CAREER: HP1 protein functions in gene regulation and chromatin structure

该项目的目标是了解分子机制，确定DNA中包含的遗传信息是否可被细胞机器访问。细胞核中的DNA被包装成一种叫做染色质的复杂结构，染色质含有多种蛋白质。作为基因调控过程的一部分，这些染色质蛋白决定存储在DNA特定部分的信息是可访问（基因“打开”）还是不可访问（基因“关闭”）。异染色质蛋白1 （HP1）蛋白家族的成员在酵母和人类等多种生物的染色质结构中起作用。具体来说，本项目将研究HP1蛋白在基因调控中的作用以及介导这一作用的分子机制。在正确的时间和地点“启动”正确的基因对生物体的生存和健康至关重要。这项研究的结果将提高对为什么这个过程有时会出错以及如何纠正的科学理解。除了进一步了解染色质外，本研究还将通过暑期实习计划培训少数民族学生在染色质生物学方面的知识，并支持专门针对少数民族和从社区大学转到四年制大学的非传统学生的课堂本科研究经验（CURE）的发展。本项目将利用缺乏HP1蛋白的果蝇系的转录组分析和染色质免疫沉淀（ChIP）实验获得的染色质状态信息来评估HP1蛋白对基因表达的影响。该分析将揭示HP1蛋白作为转录激活因子或抑制因子发挥作用的背景，以及合作效应与个体效应的区别。分析HP1募集对核小体定位、染色质组成和RNA聚合酶动力学的影响将确定HP1蛋白如何影响基因调控。这些实验将确定介导HP1蛋白对基因表达影响的分子机制。最后，对转录起始位点（TSS）相关的HP1复合物的生化分析将确定为什么在一些TSS中形成单个HP1复合物，而在其他TSS中形成多个HP1复合物。这一发现将为理解这类重要的蛋白质是如何被招募到它们的靶位点并在染色质结构和基因调控中发挥各种功能提供基础。通过利用多方面的方法，本研究将HP1蛋白在异染色质形成中的作用与其在基因调控中的作用联系起来。该项目由生物科学理事会分子和细胞生物科学部的遗传机制项目和NSF EPSCoR项目共同资助。

The goal of this project is to understand the molecular mechanisms that determine if the genetic information contained within DNA is accessible to the cellular machinery. DNA in a cell's nucleus is packaged into a complex structure called chromatin, which contains a variety of proteins. These chromatin proteins determine if the information stored in a particular portion of the DNA is accessible (genes are "turned on") or inaccessible (genes are "turned off") as part of a process called gene regulation. The members of the Heterochromatin Protein 1 (HP1) protein family function in chromatin structure in organisms as diverse as yeast and humans. Specifically, this project will examine the role of HP1 proteins in gene regulation and the molecular mechanisms mediating this role. It is essential for an organism's survival and health to "turn on" the correct genes at the correct time and place. The results from this study will improve scientific understanding of why this process sometimes goes wrong and how it might be corrected. In addition to furthering knowledge about chromatin, this study will serve to train minority students in chromatin biology through a summer internship program and support the development of a classroom undergraduate research experience (CURE) specifically targeted to minorities and non-traditional students transferring from community colleges to four-year institutions. This project will use transcriptome analysis of Drosophila lines lacking HP1 proteins and chromatin state information from chromatin immunoprecipitation (ChIP) experiments to evaluate the impact of HP1 proteins on gene expression. This analysis will reveal the contexts in which HP1 proteins function as transcriptional activators or repressors, and how cooperative effects differ from individual effect. Analysis of the impact of HP1 recruitment on nucleosome positioning, chromatin composition, and RNA polymerase dynamics will determine how HP1 proteins impact gene regulation. These experiments will identify the molecular mechanism(s) mediating the effects of HP1 proteins on gene expression. Finally, biochemical analysis of the transcription-start-site-(TSS)-associated HP1 complexes will determine why single HP1 complexes are formed at some TSSs, while others recruit multi-HP1 complexes. The findings will provide the foundation for understanding how this important class of proteins is recruited to their target sites and carries out diverse functions in chromatin structure and gene regulation. By utilizing a multi-faceted approach, this study will link the well-established role of HP1 proteins in heterochromatin formation with their role in gene regulation.This project is co-funded by the Genetic Mechanisms Program in the Division of Molecular and Cellular Biosciences in the Biological Sciences Directorate and by the NSF EPSCoR Program.