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

美国和以色列科学家之间的国际合作研究了有丝分裂的一个关键问题，即动物，植物和其他真核细胞的细胞分裂过程。 在有丝分裂过程中，染色体复制，并在分裂过程中物理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，这干扰了使用染色体中的DNA作为模板来转录信使RNA。 因此，细胞分裂会导致大多数基因表达的暂时停顿。 细胞的活动高度依赖于基因表达;例如，肺细胞和皮肤细胞具有不同的生理作用，主要是由于基因表达的差异。一个主要的未解问题是两个后代细胞在有丝分裂后恢复基因表达的遗传机制，从而恢复所有其他活动。回答这个问题的研究方法涉及实验室实验和计算分析的结合。 该项目将通过与圣地亚哥电视台加州大学合作制作专业视频，向公众介绍跨学科研究的力量。 为了扩大所有科学团体的参与，美国实验室还将与UCSD的STARS（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地传递给后代细胞至关重要。它涉及关键的变化，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脱乙酰化，并且存在核小体进入大多数转录基因的核小体耗尽区域的有丝分裂特异性脱乙酰化。另外，有丝分裂特异性组蛋白标记模式在有丝分裂期间和之后调节转录变化中的作用知之甚少。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，已经牵连在有丝分裂。 药物将用于选择性抑制每种候选酶，PI将使用基因组规模的策略来测量细胞周期期间组蛋白乙酰化的位置和数量的变化。 PI还将检查三种候选酶在有丝分裂期间和紧接有丝分裂之后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饰靶基因座的乙酰化。 这种技术将允许未来的研究详细的位点特异性有丝分裂基因的表达和再激活动力学。在一起，综合方法将使这个合作项目能够解决关于正确执行有丝分裂和分裂后重建细胞身份所需的细胞手段的关键问题。以色列项目由美国国家科学基金会和以色列两国科学基金会支持。该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响评审标准。

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.