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Establishment of Heterochromatin

异染色质的建立

基本信息

批准号：
8258797
负责人：
JANET F PARTRIDGE
金额：
$ 31.7万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8258797
关键词：
Affect Alleles Cells Centromere Chromatin Chromosomes Complex DNA Sequence Defect Dependence Development Dicer Enzyme Disease Eukaryota Event Fission Yeast Functional RNA Future Gene Mutation Gene Silencing Generations Genes Genetic Genome Genomic Imprinting Goals Health Hereditary Disease Heterochromatin Histone H3 Homologous Gene Hot Spot Human Knowledge Lead Lysine Macromolecular Complexes Maintenance Malignant Neoplasms Mammals Mediating Methylation Methyltransferase Modeling Molecular Mutation Organism Other Genetics Pathway interactions Play Process Protein Binding Proteins Publishing RNA RNA Interference Recruitment Activity Reliance Research Resolution Role Shapes Site Small Interfering RNA Structure System Testing Work X Inactivation Yeasts base cell growth cell type chromatin immunoprecipitation chromosome loss fly histone methyltransferase interest mutant novel prevent research study therapy development tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Normal cellular differentiation and development rely extensively on silencing mechanisms. Disruption of silencing can lead to genetic disorders, chromosome loss and contribute to tumorigenesis. Our long term goal is to determine the normal mechanisms that lead to establishment and maintenance of silenced regions (heterochromatin) of the genome. The goal of this proposal is to define how heterochromatin at centromeres is established. A major impediment to research on the establishment of heterochromatin has been difficulty in separating establishment from maintenance. To circumvent this problem, we utilize the exquisite genetic tractability of the fission yeast, where silenced chromatin shares many features with mammals, including reliance on similar chromatin marking systems and a shared dependence on non-coding RNA and the RNAi pathway for silencing control. Through characterization of a macromolecular complex that is important for the assembly of heterochromatin, we generated a novel mutant strain of yeast that can maintain pre-assembled heterochromatin, but cannot support its de-novo establishment. We will use this mutant to screen genes that are known to play a role in heterochromatin stability to identify those that are required for heterochromatin establishment. We have already found that one "establishment" gene that encodes a histone methyltransferase, Clr4, (the homolog of Suv39 proteins in flies and mammals) which methylates histone H3 on lysine 9 (K9) only in regions of heterochromatin. We anticipate that other "establishment" genes will regulate Clr4's recruitment to chromatin and / or its activity. Second, we will determine the DNA sequences that are required for the establishment of heterochromatin. We will define "hot-spots" for Clr4 activity using high resolution chromatin immunoprecipitation analyses, and will assess whether these sequences suffice to establish de novo heterochromatin. We will determine which establishment genes work through which establishment sequences. Finally, we will determine if K9 methylation of histone H3 suffices to establish heterochromatin, and the role that the proteins that bind this mark play in the establishment of heterochromatin. These studies will yield a basic knowledge of the mechanisms that dictate heterochromatin establishment and will provide a framework for future work directed towards understanding and developing therapies for aberrant heterochromatin assembly and disease-related silencing defects in humans. PUBLIC HEALTH RELEVANCE: The "turning-off" or silencing of specific regions of chromosomes is as important for the normal growth of cells in an organism as is "turning-on" genes. Silencing is important for cell-type identity and for enabling all cells to divide normally, such that improper silencing can contribute to genetic disorders and cancer. The proposed studies are directly relevant as they will yield a basic knowledge of silencing and help direct future work towards understanding and developing therapies for disease- related silencing defects in humans.

描述（由申请人提供）：正常细胞分化和发育广泛依赖于沉默机制。沉默的破坏可导致遗传疾病、染色体丢失并有助于肿瘤发生。我们的长期目标是确定导致基因组沉默区域（异染色质）建立和维持的正常机制。这个建议的目的是要确定如何异染色质在着丝粒建立。研究异染色质的建立的一个主要障碍是难以将异染色质的建立与维持分开。为了解决这个问题，我们利用了裂变酵母的精致遗传易处理性，其中沉默的染色质与哺乳动物共享许多特征，包括依赖于相似的染色质标记系统以及共同依赖于非编码RNA和RNAi途径进行沉默控制。通过表征的大分子复合物，这是重要的异染色质的组装，我们产生了一种新的酵母突变株，可以保持预组装的异染色质，但不能支持其从头建立。我们将使用这种突变体来筛选已知在异染色质稳定性中发挥作用的基因，以确定异染色质建立所需的基因。我们已经发现了一个编码组蛋白甲基转移酶Clr 4（果蝇和哺乳动物中Suv 39蛋白的同源物）的“建立”基因，该基因仅在异染色质区域甲基化组蛋白H3的赖氨酸9（K9）。我们预计，其他“建立”基因将调节Clr 4的招聘染色质和/或其活动。其次，我们将确定异染色质的建立所需的DNA序列。我们将使用高分辨率染色质免疫沉淀分析来定义Clr 4活性的“热点”，并将评估这些序列是否足以建立从头异染色质。我们将确定哪些建立基因通过哪些建立序列起作用。最后，我们将确定组蛋白H3的K9甲基化是否足以建立异染色质，以及结合该标记的蛋白质在异染色质建立中的作用。这些研究将产生决定异染色质建立的机制的基础知识，并将为未来的工作提供一个框架，旨在了解和开发人类异常异染色质组装和疾病相关沉默缺陷的治疗方法。公共卫生关系：染色体特定区域的“关闭”或沉默对于生物体中细胞的正常生长与“开启”基因一样重要。沉默对于细胞类型识别和使所有细胞正常分裂是重要的，因此不适当的沉默可能导致遗传疾病和癌症。拟议的研究是直接相关的，因为它们将产生沉默的基本知识，并有助于指导未来的工作，以了解和开发人类疾病相关沉默缺陷的疗法。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

SHREC Silences Heterochromatin via Distinct Remodeling and Deacetylation Modules.

DOI：
10.1016/j.molcel.2016.03.016
发表时间：
2016-04-21
期刊：
Molecular cell
影响因子：
16
作者：
Job G;Brugger C;Xu T;Lowe BR;Pfister Y;Qu C;Shanker S;Baños Sanz JI;Partridge JF;Schalch T
通讯作者：
Schalch T

Spreading the silence.

蔓延着沉默。

DOI：
10.1016/j.devcel.2009.05.002
发表时间：
2009
期刊：
Developmental cell
影响因子：
11.8
作者：
Partridge,JanetF
通讯作者：
Partridge,JanetF

Should I stay or should I go? Chromodomain proteins seal the fate of heterochromatic transcripts in fission yeast.

我应该走还是留？

DOI：
10.1016/j.molcel.2012.07.007
发表时间：
2012
期刊：
Molecular cell
影响因子：
16
作者：
Creamer,KevinM;Partridge,JanetF
通讯作者：
Partridge,JanetF

Sir2 is required for Clr4 to initiate centromeric heterochromatin assembly in fission yeast.

DOI：
10.1038/emboj.2013.143
发表时间：
2013-08-28
期刊：
EMBO JOURNAL
影响因子：
11.4
作者：
Alper, Benjamin J.;Job, Godwin;Yadav, Rajesh K.;Shanker, Sreenath;Lowe, Brandon R.;Partridge, Janet F.
通讯作者：
Partridge, Janet F.

Continuous requirement for the Clr4 complex but not RNAi for centromeric heterochromatin assembly in fission yeast harboring a disrupted RITS complex.