NSF/MCB-BSF: Characterization of the roles of mitotic associated histone deacetylation patterns

NSF/MCB-BSF：有丝分裂相关组蛋白脱乙酰化模式作用的表征

• 批准号: 2003358
• 负责人: Alon Goren
• 金额: $ 75万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003358&HistoricalAwards=false
• 关键词: NSF; MCB; BSF; Characterization; roles

This international collaboration between scientists in the U.S. and Israel investigates a key question about mitosis, the process of cell division in animal, plant, and other eukaryotic cells. During mitosis, chromosomes duplicate and have to be physically separated into two new offspring cells during division. In order to physically separate the duplicated chromosomes, the structure of the chromosomes must become condensed, which interferes with using the DNA in the chromosomes as a template to transcribe messenger RNA. Cell division thereby causes a temporary pause in most gene expression. A cell’s activities are highly dependent on gene expression; for example a lung cell and a skin cell have distinct physiological roles largely due to differences in gene expression. A major unanswered question is the genetic mechanism by which the two offspring cells restore gene expression, and thus all other activities, following mitosis. The research approach for answering this question involves a combination of laboratory experiments and computational analysis. The project will teach the public about the power of interdisciplinary research through producing professional videos in collaboration with the University of California, San Diego-TV. To broaden the participation of all groups in science, the US-based lab will also partner with UCSD’s STARS (Summer Training Academy for Research Success) program. Mitosis, a tightly regulated cell cycle phase, is critical for ensuring that cellular identity is correctly relayed to offspring cells. It involves key changes including a decrease in transcription. Initial studies showed that mitosis includes global deacetylation of histones, and that there is a mitosis-specific deacetylation of the nucleosome entering the nucleosome-depleted region of most transcribed genes. Otherwise, little is known about the roles that mitotic-specific patterns of histone marks play in regulating the transcriptional changes during and following mitosis. This project focuses on the involvement of mitotic histone deacetylations. In particular, this work focuses on three candidate histone deacetylase enzymes that are already implicated in mitosis. Pharmaceuticals will be used to inhibit selectively each of the candidate enzymes and the PIs will use genome-scale strategies to measure changes in the location and amounts of histone acetylation during the cell cycle. The PIs will also examine the extent to which the three candidates enzymes individually affect gene expression during and immediately following mitosis. Lastly, the project will establish a system to locally modify the acetylation of target loci at a specific time during the cell cycle. Such a technique would allow future studies of detailed locus-specific mitotic gene expression and reactivation kinetics. Together, the integrative approaches will enable this collaborative project to address key questions regarding the cellular means required for the proper execution of mitosis and re-establishing cellular identity after division.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.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.

美国和以色列科学家之间的这项国际合作研究了有丝分裂的一个关键问题，有丝分裂是动物、植物和其他真核细胞中的细胞分裂过程。在有丝分裂期间，染色体复制，在分裂过程中必须物理上分离成两个新的后代细胞。为了物理分离复制的染色体，染色体的结构必须变得浓缩，这干扰了以染色体中的DNA作为模板转录信使RNA。因此，细胞分裂会导致大多数基因表达暂时停顿。细胞的活动高度依赖于基因表达；例如，肺细胞和皮肤细胞在很大程度上由于基因表达的差异而具有不同的生理作用。一个主要的悬而未决的问题是，这两个后代细胞在有丝分裂后恢复基因表达的遗传机制，从而恢复了所有其他活动。回答这个问题的研究方法包括实验室实验和计算分析相结合。该项目将通过与加州大学圣地亚哥分校合作制作专业视频，向公众传授跨学科研究的力量。为了扩大所有团队对科学的参与，这个总部位于美国的实验室还将与加州大学圣地亚哥分校的STAR(夏季研究成功培训学院)计划合作。有丝分裂是一个严格调控的细胞周期阶段，对于确保细胞身份正确传递给后代细胞至关重要。它涉及到关键的变化，包括转录的减少。最初的研究表明，有丝分裂包括组蛋白的整体去乙酰化，并且存在有丝分裂特异性的核小体去乙酰化，进入大多数转录基因的核小体缺失区域。除此之外，关于组蛋白标记的有丝分裂特异性模式在调节有丝分裂过程中和有丝分裂后的转录变化中所起的作用还知之甚少。这个项目的重点是有丝分裂组蛋白去乙酰化的参与。特别是，这项工作集中在三个候选组蛋白脱乙酰酶，已经涉及有丝分裂。药物将被用来选择性地抑制每一种候选酶，PI将使用基因组规模的策略来测量组蛋白乙酰化在细胞周期中的位置和数量的变化。PI还将检查三种候选酶在有丝分裂过程中和之后立即单独影响基因表达的程度。最后，该项目将建立一个系统，在细胞周期的特定时间局部修改目标基因的乙酰化。这样的技术将使未来能够研究详细的有丝分裂基因特定位点的表达和再激活动力学。综合的方法将使这一合作项目能够解决与适当执行有丝分裂和在分裂后重建细胞身份所需的细胞手段有关的关键问题。这一美国/以色列合作项目得到了美国国家科学基金会和以色列双国科学基金会的支持。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。