权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Chromosome pairing and condensins

染色体配对和凝缩

基本信息

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
项目类别：
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

项目摘要

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(申请人提供)：我们工作的长期目标是了解不同染色体相互作用的分子机制。在这项提案中，我们特别关注反式互动是如何受到负面调控的。在包括人类在内的许多物种的体细胞和减数分裂细胞中都发现了染色体的反式相互作用。目前关于染色体反式作用的一种观点认为，蛋白质使染色体紧密相连，并允许协调基因表达或染色体分离。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基因的基因激活非常重要。在果蝇中也观察到了各种反式相互作用，无论是在体细胞中(例如，转导、反式沉默、多线染色体)，还是在减数分裂细胞中，广泛的相互作用使同源染色体在整个长度上配对。在哺乳动物、植物和真菌中，减数分裂配对对于适当的染色体分离和表观遗传过程如X失活、印迹和配对敏感的减数分裂基因沉默是重要的。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。染色体如何配对和不配对在任何生物体中基本上都是未知的。虽然已有少数蛋白质被描述为介导重组独立的减数分裂配对，但关于是什么调节体细胞染色体配对尚不清楚。目前尚不清楚体细胞和减数分裂染色体配对在结构上是否相似，或者它们是否受到相同因素的调控。我的实验室最近的工作表明，体细胞二倍体染色体配对、多线染色体配对和减数分裂染色体配对都被凝聚素II复合体拮抗。凝聚素是如何做到这一点的尚不清楚。然而，我们的观察为体细胞配对机制提供了第一个分子洞察力，我们展示了凝聚素的一种新的染色体反配对功能。凝聚素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出在所有物种中可能都很重要的基本功能。这项建议建立在我们最近关于凝集素的工作基础上。首先，我们将利用遗传学来鉴定与凝集素合作来调节多线染色体不配对的蛋白质。其次，我们将确定凝聚素调节染色体配对敏感基因在二倍体细胞中表达的机制(S)。第三，我们将确定凝聚素及其相互作用蛋白在调节减数分裂染色体配对中的功能。与公共健康相关：我们试图了解不同染色体通过物理方式相互作用的分子机制。在这项建议中，我们特别关注反式相互作用如何受到一组称为凝集素的多蛋白质复合体的负面调控。染色体相互作用导致同源序列配对，对于减数分裂中的基因调控和染色体分离是重要的。我们建议进行实验，以确定凝聚素作为染色体反配对因子的分子功能。这项拨款申请中提出的实验将对生物医学研究和人类健康的发展产生直接和重大的影响。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
通讯作者：
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
影响因子：
0
作者：
Ram,Sundaresh;Rodriguez,JeffreyJ;Bosco,Giovanni
通讯作者：
Bosco,Giovanni