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Genetic and molecular studies of Drosophila chromatin remodeling factors

果蝇染色质重塑因子的遗传和分子研究

基本信息

批准号：
8429511
负责人：
JOHN W. TAMKUN
金额：
$ 34.53万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA CRUZ
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-08-01 至 2015-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8429511
关键词：
Address Affect Animal Model Biochemical Biological Birth CHARGE syndrome Cell Fate Control Cells Chromatin Chromatin Fiber Chromatin Remodeling Factor Chromatin Structure Chromosomes Congenital Abnormality DNA DNA Packaging Development Disease Drosophila genus Drosophila melanogaster Enzymes Epigenetic Process Eukaryota Eukaryotic Cell Gene Expression Gene Silencing Genes Genetic Genetic Screening Genetic Transcription Goals Health Higher Order Chromatin Structure Histone H1 Histone H1(s)Histone H3 Histones Homeobox Genes Human ISWI In Vitro Laboratories Lead Learning Linker DNA Lysine Malignant Neoplasms Methods Methylation Modification Molecular Genetics Mutation Nucleosomes Organism Play Polycomb Positioning Attribute Process Proteins Recruitment Activity Repression Role Structure Testing Transcription Elongation Work cell growth regulation chromatin modification chromatin remodeling developmental disease fly gene repression genetic regulatory protein genome-wide human disease in vivo pluripotency prevent public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Nucleosomes and other components of chromatin can repress transcription by blocking the access of transcription factors and other regulatory proteins to DNA. Interactions between nucleosomes and linker histones promote the formation of 30 nm fibers and increasingly compact forms of higher-order chromatin structure, further limiting the access of regulatory proteins to DNA. Alterations in chromatin structure lead to a variety of human diseases, including cancer and birth defects. Although tremendous progress has been made toward determining the mechanism of action of chromatin-remodeling factors and histone-modifying enzymes, much remains to be learned about how they regulate transcription by altering the structure and spacing of nucleosomes. Even less is known about how higher-order chromatin structure is regulated and used to control gene expression in eukaryotic cells. To address these important issues, our laboratory uses Drosophila melanogaster as a model organism to study the function of chromatin-remodeling and modifying enzymes. Much of our work has been focused on the roles of Polycomb and trithorax group in transcription and development. Polycomb group proteins play important roles in the regulation of cellular pluripotency and differentiation by methylating lysine 27 of histone H3 over broad chromatin domains. This chromatin modification plays a key role in epigenetic gene silencing in organisms ranging from flies to humans. A key issue concerns how Polycomb group repression is overcome to permit the expression of genes required for differentiation. Recent studies in our lab have suggested that Kismet (KIS), an ATP-dependent chromatin-remodeling factor, plays an important role in this process by preventing the spread of H3K27 methylation into active genes. To test this hypothesis, we will compare the genome-wide distributions of KIS and H3K27 methylation and determine if KIS acts as a barrier to the spread of the repressive modification. Other studies in our laboratory have suggested that another chromatin-remodeling factor, Imitation-SWI (ISWI), plays a global role in chromatin compaction and transcriptional repression by promoting the association of the linker histone H1 with chromatin. To test this hypothesis, we will compare changes in gene expression resulting from the loss of ISWI and histone H1 function in vivo. We will also use complementary genetic, biochemical and cell biological approaches to determine how ISWI promotes the association of histone H1 with chromatin and identify other factors involved in this process. By studying multiple chromatin- remodeling factors in a single model organism, we will gain a much better understanding of their roles in transcription, development and disease.

描述（由申请人提供）：核小体和染色质的其他成分可以通过阻断转录因子和其他调节蛋白接触 DNA 来抑制转录。核小体和连接组蛋白之间的相互作用促进了 30 nm 纤维的形成和日益紧凑的高阶染色质结构，进一步限制了调节蛋白与 DNA 的接触。染色质结构的改变会导致多种人类疾病，包括癌症和出生缺陷。尽管在确定染色质重塑因子和组蛋白修饰酶的作用机制方面已经取得了巨大进展，但关于它们如何通过改变核小体的结构和间距来调节转录，仍有许多待了解。关于如何调节高级染色质结构并用于控制真核细胞中的基因表达，人们知之甚少。为了解决这些重要问题，我们实验室使用黑腹果蝇作为模式生物来研究染色质重塑和修饰酶的功能。我们的大部分工作都集中在 Polycomb 和 trithorax 群在转录和发育中的作用。 Polycomb 组蛋白通过在广泛的染色质域上甲基化组蛋白 H3 的赖氨酸 27，在细胞多能性和分化的调节中发挥重要作用。这种染色质修饰在从果蝇到人类等生物体的表观遗传基因沉默中发挥着关键作用。一个关键问题涉及如何克服多梳组抑制以允许分化所需的基因表达。我们实验室最近的研究表明，Kismet (KIS)，一种 ATP 依赖性染色质重塑因子，通过阻止 H3K27 甲基化扩散到活性基因中，在此过程中发挥着重要作用。为了检验这一假设，我们将比较 KIS 和 H3K27 甲基化的全基因组分布，并确定 KIS 是否充当抑制性修饰传播的障碍。我们实验室的其他研究表明，另一种染色质重塑因子 Imitation-SWI (ISWI) 通过促进连接组蛋白 H1 与染色质的结合，在染色质压缩和转录抑制中发挥全局作用。为了验证这一假设，我们将比较体内 ISWI 和组蛋白 H1 功能丧失导致的基因表达变化。我们还将使用互补的遗传、生化和细胞生物学方法来确定 ISWI 如何促进组蛋白 H1 与染色质的关联，并确定参与此过程的其他因素。通过研究单一模型生物体中的多种染色质重塑因子，我们将更好地了解它们在转录、发育和疾病中的作用。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Drosophila ISWI regulates the association of histone H1 with interphase chromosomes in vivo.

果蝇 ISWI 在体内调节组蛋白 H1 与间期染色体的关联。

DOI：
10.1534/genetics.109.102053
发表时间：
2009
期刊：
Genetics
影响因子：
3.3
作者：
Siriaco,Giorgia;Deuring,Renate;Chioda,Mariacristina;Becker,PeterB;Tamkun,JohnW
通讯作者：
Tamkun,JohnW

ISWI regulates higher-order chromatin structure and histone H1 assembly in vivo.

DOI：
10.1371/journal.pbio.0050232
发表时间：
2007-09
期刊：
PLoS biology
影响因子：
9.8
作者：
Corona DF;Siriaco G;Armstrong JA;Snarskaya N;McClymont SA;Scott MP;Tamkun JW
通讯作者：
Tamkun JW

Drosophila Kismet regulates histone H3 lysine 27 methylation and early elongation by RNA polymerase II.

果蝇Kismet调节组蛋白H3赖氨酸27甲基化和RNA聚合酶II的早期延伸。