OXIDATIVE STRESS AND BASE MODIFICATIONS IN REGULATORY DNA
调控 DNA 中的氧化应激和碱基修饰
基本信息
- 批准号:9922326
- 负责人:
- 金额:$ 30.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAntibodiesBase Excision RepairsBinding SitesBreastCancer cell lineCancerousCell Culture TechniquesCell LineCellsChemicalsChemistryChromatinColonCoupledCpG IslandsDNADNA Modification ProcessDNA Polymerase IIDNA lesionDNA sequencingDataDiabetes MellitusDiseaseEnzymesEpigenetic ProcessExposure toFlavinsG-QuartetsGene ExpressionGenesGenomeGenomic DNAGlioblastomaGuanineHelicobacter pyloriHemeHistone AcetylationHistone Deacetylase InhibitorHistonesHydrogen PeroxideHypersensitivityInfectionInflammationInflammatory ResponseInjuryIntronsKDM1A geneLaboratoriesLeadLesionLigationLinkLocationLysineMalignant NeoplasmsMetabolic DiseasesMetabolismMethodsMissionMitochondrial DNAModificationMonitorMutagenesisNucleic Acid Regulatory SequencesNucleotidesOGG1 geneOutcomeOxidative StressOxidesPathway interactionsPlasmidsPlayProcessPromoter RegionsPublic HealthRNARadiationReactive Oxygen SpeciesResearchResolutionRoleSiteSmall Interfering RNAStructureTNF geneToxic Environmental SubstancesTranscriptTraumatic Brain InjuryUnited States National Institutes of HealthUntranslated RegionsWorkage relatedbasebisulfite sequencingchromatin remodelingexperimental studygene inductiongenome sequencinggenomic dataknock-downmammalian genomemembermethylation patternnervous system disordernext generation sequencingnoveloverexpressionoxidationpromoterstressortranscription factortranscriptome sequencingwhole genome
项目摘要
ABSTRACT
Reactive oxygen species (ROS) with the potential to modify genomic and mitochondrial DNA are formed
from exposure to radiation, environmental toxins, and endogenous chemistries resulting from
inflammation, allergies, injury and metabolism. Oxidative stress leads to myriad effects on the cell,
notably changes in gene expression and mutagenesis, and ultimately contributes to numerous age-
related diseases including cancer, neurological disorders, diabetes and others. Recent work in this
laboratory has shown that the common guanine oxidation product 8-oxo-7,8-dihydroguanine (OG) is not
only a pre-mutagenic lesion, but also a base modification that impacts gene expression when present in
potential G-quadruplex-forming sequences of regulatory regions of the genome. This epigenetic-like
DNA modification is proposed to be written by chromatin remodeling in addition to exposure to ROS,
while it is read and erased by the base excision repair (BER) pathway, including OGG1 and APE1,
critical members of BER. The specific aims of this project will first augment recent results toward whole-
genome sequencing of DNA for OG at single-nucleotide resolution via “OG-Seq” and related methods for
other modifications read by BER. The approach uses a novel chemical ligation strategy that is shown to
be superior to OG antibodies in providing unbiased pull-down of OG-containing fragments for PCR
amplification and next-generation sequencing. The sequencing methods will be applied in Aim 2 to
address the hypothesis that base modifications resulting from oxidative stress are non-uniformly
distributed in the genome, that G-quadruplex sequences are hotspots for oxidation, and that they
subsequently impact gene induction. Both cancerous and noncancerous cell lines will be studied using
various types of oxidative stress that mimic, for example, the inflammatory response or heme overload.
The impact of chromatin remodeler LSD1 and chromatin opening via HDAC inhibitors will be examined in
Aim 3. The overall outcome will be a deeper understanding of the relationship between oxidative stress
and disease by defining where and when these epigenetic-like modifications occur in DNA.
摘要
形成了可能修饰基因组和线粒体DNA的活性氧物种(ROS)
暴露于辐射、环境毒素和由以下因素引起的内源性化学物质
炎症、过敏、损伤和新陈代谢。氧化应激会对细胞产生多种影响,
基因表达和突变的显著变化,并最终导致许多年龄-
相关疾病,包括癌症、神经疾病、糖尿病和其他。最近在这方面的工作
实验室已证明,常见的鸟嘌呤氧化产物8-氧代-7,8-二氢鸟嘌呤(OG)不是
不仅是诱变前的损伤,而且还有碱基修饰,当存在于
基因组调节区的潜在G-四链形成序列。这种表观遗传学
DNA修饰被认为是除了暴露于ROS之外还通过染色质重塑来写入,
虽然它被碱基切除修复(BER)途径(包括OGG1和APE1)读取和擦除,
BER的关键成员。该项目的具体目标首先将把最近的成果扩大到整体--
通过“OG-Seq”和相关方法在单核苷酸分辨率下对OG的DNA进行基因组测序
BER读取的其他修改。该方法使用了一种新的化学连接策略,该策略被证明
在为聚合酶链式反应提供无偏见的含有OG的片段方面优于OG抗体
扩增和下一代测序。排序方法将在目标2中应用于
解决氧化应激引起的碱基修饰不均匀的假设
分布在基因组中,G-四链序列是氧化的热点,它们
随后影响基因诱导。癌症和非癌症细胞系都将用
各种类型的氧化应激,例如,模仿炎症反应或血红素超载。
染色质重构体LSD1和通过HDAC抑制剂开放染色质的影响将在
目标3.总体结果将是对氧化应激之间的关系有更深的理解
通过定义DNA中这些表观遗传性修饰发生的地点和时间来确定疾病。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Cynthia J Burrows其他文献
Cynthia J Burrows的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Cynthia J Burrows', 18)}}的其他基金
Chemical Modifications in Regulatory Regions of DNA and RNA
DNA 和 RNA 调控区域的化学修饰
- 批准号:
10406114 - 财政年份:2022
- 资助金额:
$ 30.5万 - 项目类别:
Chemical Modifications in Regulatory Regions of DNA and RNA
DNA 和 RNA 调控区域的化学修饰
- 批准号:
10629233 - 财政年份:2022
- 资助金额:
$ 30.5万 - 项目类别:
OXIDATIVE STRESS AND BASE MODIFICATIONS IN REGULATORY DNA
调控 DNA 中的氧化应激和碱基修饰
- 批准号:
10153820 - 财政年份:2018
- 资助金额:
$ 30.5万 - 项目类别:
Nanopore Detection of DNA and RNA Modifications
DNA 和 RNA 修饰的纳米孔检测
- 批准号:
9134159 - 财政年份:2011
- 资助金额:
$ 30.5万 - 项目类别:
Nanopore Detection of DNA and RNA Modifications
DNA 和 RNA 修饰的纳米孔检测
- 批准号:
8887872 - 财政年份:2011
- 资助金额:
$ 30.5万 - 项目类别:
Interplay of RNA Structural Motifs with Base Modifications
RNA 结构基序与碱基修饰的相互作用
- 批准号:
10246857 - 财政年份:2011
- 资助金额:
$ 30.5万 - 项目类别: