Chromosome pairing and condensins

染色体配对和凝缩

• 批准号: 8518870
• 负责人: GIOVANNI BOSCO
• 金额: $ 27.04万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518870
• 关键词: ATP phosphohydrolase; Applications Grants; Bacteria; Biological Assay; Biomedical Research; Cells; Chromatids; Chromosome Pairing; Chromosome Segregation; Chromosomes; Complex; DNA; DNA repair protein; Diploid Cells; Diploidy; Drosophila genus; Enhancers; Epigenetic Process; Female; Gene Activation; Gene Expression; Gene Expression Regulation; Gene Silencing; Genes; Genetic; Genetic Recombination; Genetic Transcription; Goals; Health; Human; Interphase Cell; Laboratories; Lead; Length; Mammals; Mediating; Meiosis; Modeling; Molecular; Mus; Nurses; Organism; Proteins; RNA; RNA Interference; Receptor Gene; Regulation; Role; Salivary Glands; Sequence Homologs; Somatic Cell; Synaptonemal Complex; Transgenic Organisms; Work; X Inactivation; condensin; imprint; in vivo; insight; male; novel; olfactory receptor; plant fungi; protein complex; research study; segregation; tool

DESCRIPTION (provided by applicant): The long term goal of our work is to understand the molecular mechanisms through which different chromosomes physically interact. In this proposal we focus specifically on how trans-interactions are negatively regulated. Chromosomal trans-interactions have been seen in somatic cells and meiotic cells of many species, including human. A current view of chromosome trans-interactions posits that proteins bring chromosomes into intimate proximity and allow coordination of gene expression or chromosome segregation. For example, chromosome trans-interactions are important for gene activation in the mouse olfactory receptor gene and the mouse TH2 LCR locus. A variety of trans-interactions also have been observed in Drosophila, both in somatic cells (e.g.transvection, trans-silencing, polytene chromosomes) and in meiotic cells where extensive interactions pair homologous chromosomes throughout their lengths. Meiotic pairing is important for proper chromosome segregation and for epigenetic processes such as X-inactivation, imprinting, and pairing-sensitive meiotic gene silencing in mammals, plants and fungi. Both somatic and meiotic pairing can occur by mechanisms that are completely independent of DNA recombination and repair proteins. How chromosomes pair and unpair is largely unknown in any organism. Although a handful of proteins have been described to mediate recombination independent meiotic pairing, there is nothing known about what regulates somatic chromosome pairing. It is not known whether somatic and meiotic chromosome pairing are structurally similar or if they are regulated by the same factors. Work from my laboratory has recently demonstrated that pairing of somatic diploid chromosomes, polytene chromosome pairing and meiotic chromosome pairing are all antagonized by the condensin II complex. How condensins do this is unclear. However, our observations provide the first molecular insight into a somatic pairing mechanism, and we demonstrate a novel chromosome anti-pairing function for condensins. Condensins are conserved from bacteria to humans, therefore understanding how they regulate chromosome interactions will reveal basic functions likely to be important in all species. This proposal builds on our recent work on condensin. First, we will use genetics to identify the proteins that cooperate with condensins to regulate polytene chromosome unpairing. Second, we will determine the mechanism(s) through which condensins regulate chromosome pairing sensitive gene expression in diploid somatic cells. Third, we will determine the function of condensins, and their interacting proteins, in regulating meiotic chromosome pairing. PUBLIC HEALTH RELEVANCE: We seek to understand the molecular mechanisms through which different chromosomes physically interact. In this proposal we focus specifically on how trans- interactions are negatively regulated by a set of multi-protein complexes known as condensins. Chromosome interactions leading to pairing of homologous sequences is important for gene regulation and chromosome segregation in meiosis. We propose experiments that will determine the molecular function of condensins as chromosome anti-pairing factors. The experiments proposed in this grant application will have a direct and significant impact on the advancement of biomedical research and human health.

描述（由申请人提供）：我们工作的长期目标是了解不同染色体物理相互作用的分子机制。在本提案中，我们特别关注跨交互是如何受到负面调节的。染色体反式相互作用已在包括人类在内的许多物种的体细胞和减数分裂细胞中发现。目前关于染色体反式相互作用的观点认为，蛋白质使染色体接近并允许基因表达或染色体分离的协调。例如，染色体反式相互作用对于小鼠嗅觉受体基因和小鼠TH2 LCR位点的基因激活是重要的。在果蝇中也观察到多种反式相互作用，包括体细胞（如横断、反式沉默、多丝染色体）和减数分裂细胞，在这些细胞中，广泛的相互作用对同源染色体进行配对。在哺乳动物、植物和真菌中，减数分裂配对对于正确的染色体分离和表观遗传过程（如x失活、印记和配对敏感的减数分裂基因沉默）非常重要。体细胞配对和减数分裂配对都可以通过完全独立于DNA重组和修复蛋白的机制发生。在任何生物体中，染色体如何配对和不配对在很大程度上是未知的。虽然已经描述了少数蛋白质介导重组独立的减数分裂配对，但对于什么调节体细胞染色体配对还一无所知。目前尚不清楚体细胞和减数分裂染色体配对是否在结构上相似，或者它们是否受相同因素的调节。我的实验室最近的研究表明，体细胞二倍体染色体配对、多丝染色体配对和减数分裂染色体配对都受到凝缩蛋白II复合体的拮抗。凝缩蛋白是如何做到这一点的尚不清楚。然而，我们的观察提供了对体细胞配对机制的第一个分子洞察力，我们证明了一种新的染色体反配对功能的凝聚蛋白。凝聚蛋白从细菌到人类都是保守的，因此了解它们如何调节染色体相互作用将揭示在所有物种中可能很重要的基本功能。这个建议是建立在我们最近对冷凝物的研究基础上的。首先，我们将利用遗传学鉴定与凝聚蛋白合作调节多烯染色体解偶的蛋白质。其次，我们将确定凝缩蛋白调控二倍体体细胞中染色体配对敏感基因表达的机制。第三，我们将确定凝缩蛋白及其相互作用蛋白在调节减数分裂染色体配对中的功能。公共卫生相关性：我们试图了解不同染色体物理相互作用的分子机制。在这个建议中，我们特别关注反式相互作用是如何被一组多蛋白复合物称为缩合蛋白负调控的。染色体相互作用导致同源序列配对对减数分裂中基因调控和染色体分离具有重要意义。我们提出的实验将确定凝缩蛋白作为染色体反配对因子的分子功能。本拨款申请中提出的实验将对生物医学研究和人类健康的进步产生直接和重大的影响。

项目成果

Chromosome pairing: a hidden treasure no more.

• DOI: 10.1371/journal.pgen.1002737
• 发表时间: 2012
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Bosco G

Condensin II promotes the formation of chromosome territories by inducing axial compaction of polyploid interphase chromosomes.

• DOI: 10.1371/journal.pgen.1002873
• 发表时间: 2012
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Bauer CR;Hartl TA;Bosco G
• 通讯作者: Bosco G

Drosophila casein kinase I alpha regulates homolog pairing and genome organization by modulating condensin II subunit Cap-H2 levels.

• DOI: 10.1371/journal.pgen.1005014
• 发表时间: 2015
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Nguyen HQ;Nye J;Buster DW;Klebba JE;Rogers GC;Bosco G
• 通讯作者: Bosco G

High SINE RNA Expression Correlates with Post-Transcriptional Downregulation of BRCA1.

• DOI: 10.3390/genes4020226
• 发表时间: 2013-04-29
• 期刊: Genes
• 影响因子: 3.5
• 作者: Peterson M;Chandler VL;Bosco G
• 通讯作者: Bosco G

Segmentation and detection of fluorescent 3D spots.

荧光 3D 斑点的分割和检测。

• DOI: 10.1002/cyto.a.22017
• 发表时间: 2012
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology
• 作者: Ram,Sundaresh;Rodriguez,JeffreyJ;Bosco,Giovanni
• 通讯作者: Bosco,Giovanni