Mechanisms of heterochromatin targeting and epigenetic genome regulation
异染色质靶向和表观遗传基因组调控机制
基本信息
- 批准号:10337814
- 负责人:
- 金额:$ 42.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-01-20 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AddressBase PairingBiochemicalBiologicalCell NucleusCellsChromatinDevelopmentDiseaseEpigenetic ProcessGene ExpressionGene Expression ProfileGene Expression RegulationGenesGenomeGenome StabilityGenomic approachGoalsHeritabilityHeterochromatinHistonesHumanHuman GenomeInterventionJunk DNALeadLinkMalignant NeoplasmsMediatingMessenger RNAModelingMolecularMolecular Mechanisms of ActionNuclearPathway interactionsPharmacologyPublic HealthRNARNA-Binding ProteinsReaderRegulationResearchStudy modelsSystemTranscriptUntranslated RNAWorkgene repressionhuman diseaseinsightpiRNAprograms
项目摘要
PROJECT SUMMARY
Epigenetic gene repression by heterochromatin is necessary for multi-cellular organismal development
and genome stability. Mis-regulation of heterochromatin is a cause of multiple diseases through perturbed gene
expression patterns. The long-term goals of our research program are to determine at a molecular level how
noncoding RNAs (ncRNAs) participate in heterochromatin formation and function. Many ncRNAs act in the
nucleus to regulate gene expression through association with chromatin regulatory machinery. We and others
have shown that certain RNA-mediated heterochromatin pathways require intermolecular RNA-RNA interactions
between ncRNAs and nascent RNA that serve as the trigger to form heterochromatin. However, many systems
where RNA is implicated have unexplored molecular mechanisms of action. We will address three high-level
major outstanding questions in the field: 1) Which heterochromatin systems are controlled through RNA-RNA
interactions? 2) How is heterochromatin built around nascent RNA? 3) How are RNA binding proteins re-
purposed from mRNA processing functions to contribute to RNA-mediated heterochromatin formation? Our
research program focuses on multiple heterochromatin systems that incorporate different species of noncoding
RNAs. We study long noncoding RNAs (lncRNAs), such as HOTAIR and pericentromeric transcripts, which can
inhibit heterochromatic histone modifiers to control their activity. In addition, we have developed the first
biochemical system to study the human nuclear piRNA pathway, which uses base-pairing of the small piRNA to
target nascent transcripts of repeats that then are suppressed via heterochromatin. Finally, we address how
RBPs such as the N6-methyladenosine reader YTHDC1 can work with ncRNAs to promote gene repression.
We use biochemical, structural, cell biological, and genomic approaches to study these models of RNA-regulated
heterochromatin. Mechanistic insight into these pathways will provide a fuller understanding of how they work
normally and in disease, which will prove useful in targeting for pharmacological intervention.
Relevance to public health
Noncoding RNAs are produced from regions of the human genome originally thought to be "junk" DNA. Many
ncRNAs participate in epigenetic mechanisms of gene regulation and mis-regulation can lead to diseases such
as cancer. ncRNAs are therefore clear candidates to provide a missing link to understanding the molecular
mechanisms of many human diseases for which there is a "hidden heritability" factor that has not yet been
identified.
项目摘要
异染色质对表观遗传基因的抑制是多细胞生物发育所必需的
和基因组稳定性。异染色质的错误调控是通过基因干扰引起多种疾病的原因之一
表达模式我们研究计划的长期目标是在分子水平上确定
非编码RNA(ncRNA)参与异染色质的形成和功能。许多ncRNA在
细胞核通过与染色质调节机制的关联来调节基因表达。我们和其他人
已经表明某些RNA介导的异染色质途径需要分子间RNA-RNA相互作用
在ncRNA和新生RNA之间,它们是形成异染色质的触发器。然而,许多系统
其中涉及RNA具有未探索的分子作用机制。我们将讨论三个高级别
该领域的主要突出问题:1)哪些异染色质系统是通过RNA-RNA控制的
互动?2)异染色质是如何围绕新生RNA构建的?3)RNA结合蛋白是如何被...
目的是从mRNA加工功能,以促进RNA介导的异染色质形成?我们
研究计划的重点是多异染色质系统,包括不同种类的非编码
RNA。我们研究长链非编码RNA(lncRNA),如HOTAIR和近着丝粒转录本,它们可以
抑制异染色质组蛋白修饰剂以控制其活性。此外,我们还开发了第一个
这是一个生物化学系统来研究人类核皮尔纳途径,它使用小皮尔纳的碱基配对,
靶向重复的新生转录物,然后通过异染色质抑制。最后,我们讨论如何
RBP如N6-甲基腺苷读取器YTHDC 1可以与ncRNA一起工作以促进基因抑制。
我们使用生物化学、结构、细胞生物学和基因组学方法来研究这些RNA调节的模型。
异染色质对这些途径的机制性洞察将提供对它们如何工作的更全面的理解
在正常情况下和疾病中,这将证明在靶向药物干预方面是有用的。
与公共卫生的相关性
非编码RNA是由人类基因组中最初被认为是“垃圾”DNA的区域产生的。许多
ncRNA参与基因调控的表观遗传机制,而错误调控可导致疾病,
癌症因此,ncRNA是明确的候选者,以提供理解分子生物学的缺失环节。
许多人类疾病的机制,其中有一个“隐藏的遗传性”因素,尚未被发现。
鉴定
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Aaron M. Johnson其他文献
Effects of Age and Exercise on Neuromuscular Junction Plasticity in Muscles of Swallowing and Voice
年龄和运动对吞咽和发声肌肉神经肌肉接头可塑性的影响
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:0
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Developing a Simple Model for Sand-Tool Interaction and Autonomously Shaping Sand
开发沙具交互和自主塑造沙子的简单模型
- DOI:
- 发表时间:
2019 - 期刊:
- 影响因子:0
- 作者:
Wooshik Kim;C. Pavlov;Aaron M. Johnson - 通讯作者:
Aaron M. Johnson
Convergent iLQR for Safe Trajectory Planning and Control of Legged Robots
用于腿式机器人安全轨迹规划和控制的收敛 iLQR
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:0
- 作者:
James Zhu;J. Payne;Aaron M. Johnson - 通讯作者:
Aaron M. Johnson
Effects of Historical Recording Technology on Vibrato in Modern-Day Opera Singers.
历史录音技术对现代歌剧演员颤音的影响。
- DOI:
- 发表时间:
2020 - 期刊:
- 影响因子:2.2
- 作者:
Joshua D. Glasner;Aaron M. Johnson - 通讯作者:
Aaron M. Johnson
Basic Science: The Foundation of Evidence-Based Voice Therapy
基础科学:循证声音治疗的基础
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
Aaron M. Johnson - 通讯作者:
Aaron M. Johnson
Aaron M. Johnson的其他文献
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{{ truncateString('Aaron M. Johnson', 18)}}的其他基金
Disrupting long noncoding RNA methylation to elicit antimorph behavior in breast cancer
破坏长链非编码 RNA 甲基化以引发乳腺癌的反形态行为
- 批准号:
10646843 - 财政年份:2023
- 资助金额:
$ 42.22万 - 项目类别:
Mechanisms of heterochromatin targeting and epigenetic genome regulation
异染色质靶向和表观遗传基因组调控机制
- 批准号:
10552566 - 财政年份:2022
- 资助金额:
$ 42.22万 - 项目类别:
Mechanisms of heterochromatin targeting and epigenetic genome regulation
异染色质靶向和表观遗传基因组调控机制
- 批准号:
9142004 - 财政年份:2016
- 资助金额:
$ 42.22万 - 项目类别:
Comprehensive Characterization of Heterochromatin Domains
异染色质结构域的综合表征
- 批准号:
7953144 - 财政年份:2010
- 资助金额:
$ 42.22万 - 项目类别:
Comprehensive Characterization of Heterochromatin Domains
异染色质结构域的综合表征
- 批准号:
8132400 - 财政年份:2010
- 资助金额:
$ 42.22万 - 项目类别:
Comprehensive Characterization of Heterochromatin Domains
异染色质结构域的综合表征
- 批准号:
8392028 - 财政年份:2010
- 资助金额:
$ 42.22万 - 项目类别:
Comprehensive Characterization of Heterochromatin Domains
异染色质结构域的综合表征
- 批准号:
8424267 - 财政年份:2010
- 资助金额:
$ 42.22万 - 项目类别:
Comprehensive Characterization of Heterochromatin Domains
异染色质结构域的综合表征
- 批准号:
8607964 - 财政年份:2010
- 资助金额:
$ 42.22万 - 项目类别:
Mechanistic Studies of silent chromatin spreading
沉默染色质扩散的机制研究
- 批准号:
7155848 - 财政年份:2006
- 资助金额:
$ 42.22万 - 项目类别:
Mechanistic Studies of silent chromatin spreading
沉默染色质扩散的机制研究
- 批准号:
7285996 - 财政年份:2006
- 资助金额:
$ 42.22万 - 项目类别:
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