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（由申请人提供）：我们工作的长期目标是了解不同染色体在物理相互作用的分子机制。在此提案中，我们专门关注跨性别互动的负面调节。在包括人类在内的许多物种的体细胞和减数分裂细胞中已经看到了染色体跨性交。当前的染色体跨性相互作用的观点认为，蛋白质使染色体成为亲密接近，并允许基因表达或染色体分离的协调。例如，染色体跨性相互作用对于小鼠嗅觉受体基因和小鼠Th2 LCR基因座中的基因激活很重要。在果蝇中也观察到了各种跨性相互作用，无论是在体细胞中（例如，转传，反传感，反传感，多丁烯染色体）和减数分裂细胞，在整个长度上，广泛的相互作用是同源染色体。减数分裂配对对于适当的染色体分离和表观遗传过程至关重要，例如在哺乳动物，植物和真菌中对X灭活，印迹和对成对敏感的减数分裂基因沉默。体细胞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来进行。在任何生物体中，染色体对染色体如何配对和不遗聚是未知的。尽管已经描述了少数蛋白质可以介导重组独立的减数分裂配对，但对哪种调节体细胞染色体配对的了解尚不了解。尚不清楚体细胞和减数分裂染色体配对在结构上是相似的，还是由相同因素调节。我的实验室的工作最近表明，体二倍体染色体，多晶染色体配对和减数分裂染色体配对都与Condensin II复合物进行了拮抗。冷凝剂的工作方式尚不清楚。但是，我们的观察结果为躯体配对机制提供了第一个分子见解，我们展示了一种新型的冷凝蛋白染色体抗生成功能。冷凝蛋白是从细菌到人的保守的，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。这项提案是基于我们最近在Condensin的工作。首先，我们将使用遗传学来鉴定与冷凝蛋白合作的蛋白质，以调节不成熟的多晶染色体。其次，我们将确定冷凝蛋白调节二倍体细胞中染色体敏感基因表达的机制。第三，我们将确定冷凝蛋白及其相互作用蛋白在调节减数分裂染色体配对方面的功能。公共卫生相关性：我们试图了解不同染色体在物理相互作用的分子机制。在此提案中，我们专门关注转移相互作用如何受到一组称为冷凝蛋白的多蛋白络合物的负调节。导致同源序列配对的染色体相互作用对于减数分裂中的基因调节和染色体分离很重要。我们提出的实验将确定冷凝蛋白作为染色体抗生成因子的分子功能。本赠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

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

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