Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome inResponse to Environmental Arsenic Exposure
建立响应环境砷暴露的致癌 3D 基因组的分子基础
基本信息
- 批准号:10594774
- 负责人:
- 金额:$ 59.27万
- 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:2022-03-19 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAffectAlternative SplicingAnimal ModelArsenicAutomobile DrivingBindingBinding SitesBiochemicalBiologyCCCTC-binding factorCancer BiologyCarcinogensCell modelCellsCessation of lifeChIP-seqChromatinChromatin LoopChromatin StructureDNADNA BindingDNA DamageDNA MethylationDNA Modification MethylasesDevelopmentDiagnosisDiagnosticDimensionsDiseaseEnhancersEnvironmentEnvironmental ExposureEnvironmental PollutantsEpigenetic ProcessEtiologyExposure toGene ExpressionGene Expression ProfileGene Expression RegulationGenesGenomeGenomic SegmentGenomicsGoalsGrowth and Development functionHealthHistonesHumanHybridsKnowledgeLightMalignant NeoplasmsMapsMediatingMetalsModelingMolecularMutationNeoplasm MetastasisNucleosomesOncogenicOrganismPathogenesisPathogenicityPathologyPatternPersonsPharmaceutical PreparationsPlayProcessProteinsReactive Oxygen SpeciesRiskRoleSiteSpliced GenesTechniquesTestingTherapeuticTherapeutic AgentsTranscription InitiationVariantWorkWritingarsenic carcinogenesisbasecarcinogenesiscarcinogenicitychromatin remodelingdisorder preventionepigenomeepigenomicsepithelial to mesenchymal transitiongene regulatory networkgenome-widein vivometaplastic cell transformationpollutantpreventpromotertargeted treatmenttherapeutic developmentthree dimensional structuretool
项目摘要
Abstract
Establishing the influence of pollutants on genome function is essential in defining their impact on human
health. Environmental pollutants such as inorganic arsenic (iAs) are responsible for over thirteen million deaths
yearly. Importantly, 24% of the diseases caused by environmental exposures might have been avoided by
disease prevention, diagnosis and the development of safer metal-based therapeutic agents. In order to
understand how these pollutants cause disease, we need to understand how pollutants change gene
expression. Proper gene regulation is essential for normal growth, development and etiology of diseases such
as cancer. Eukaryotic DNA stored as chromatin plays an integral role in gene regulation. At the one-
dimensional (1D) level, chromatin is found as nucleosomes and at the three dimensional level (3D), chromatin
is found in loops and topological domains, both of which regulate gene expression by allowing accessibility to
the DNA wrapped up as chromatin. Inorganic arsenic is a ubiquitous metal that impacts gene regulation
through modulating the epigenome. We recently provided the epigenetic landscape (DNA methylation, histone
PTMs and histone variants) mediated by iAs. This landscape though important, makes it difficult to decipher
whether the observed effects on gene activity are due to local changes in epigenetic environments, or effects
caused by remote changes several kilobases away, such as the activity of enhancer(s). Additionally, the effect
of the 3D chromatin structure supersedes that at the 1D chromatin level. This 3D information is mediated by
CTCF, known as a ‘master weaver’ of the genome, and any dysregulation of the CTCF binding alters this 3D
structure, resulting in gene dysregulation. We recently showed that iAs selectively inhibits CTCF from binding
to some of its target sites and instigating oncogenic expression patterns. Interestingly, carcinogenesis is not a
linear process but involves a several hybrid in-between stages till final cancer state. We therefore hypothesize
that by inhibiting CTCF binding, iAs reorganizes the genome to maintain specific topologically-activated
domains at the 3D chromatin structure to drive specific oncogenic potentials. To test this hypothesis, we will
map CTCF binding (Aim 1), chromatin 3D (Aim 2) and ChIP-seq of histone marks (Aim 3) as cells undergo iAs-
mediated carcinogenesis. The knowledge derived from the proposed studies will allow us to characterize the
resulting gene regulatory network mediated by iAs exposure, and allow us to unambiguously anchor iAs
exposure to changes in the CTCF interactome in the process of iAs-mediated cancer. Additionally, these
studies will allow us to decipher how iAs initiates, establishes and maintains particular chromatin signatures
that ultimately drive gene expression in iAs pathogenesis. Such studies are critically needed for the
identification of translational targets and the development of therapeutic drugs needed in iAs-disease
pathology.
摘要
项目成果
期刊论文数量(0)
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Yvonne Nsokika Fondufe-Mittendorf其他文献
Yvonne Nsokika Fondufe-Mittendorf的其他文献
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{{ truncateString('Yvonne Nsokika Fondufe-Mittendorf', 18)}}的其他基金
Molecular mechanisms of iAs-mediated carcinogenesis through the lens of histone H2B variants
通过组蛋白 H2B 变异观察 iAs 介导的致癌作用的分子机制
- 批准号:
10616739 - 财政年份:2022
- 资助金额:
$ 59.27万 - 项目类别:
Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome inResponse to Environmental Arsenic Exposure
建立响应环境砷暴露的致癌 3D 基因组的分子基础
- 批准号:
10610974 - 财政年份:2022
- 资助金额:
$ 59.27万 - 项目类别:
Molecular Underpinnings in the Establishment of an Oncogenic 3D Genome in Response to Environmental Arsenic Exposure
建立响应环境砷暴露的致癌 3D 基因组的分子基础
- 批准号:
10159289 - 财政年份:2020
- 资助金额:
$ 59.27万 - 项目类别:
Diversity Supplement: The Role of Chromatin Structural and Epigenetic Changes in Arsenic-Induced Gene Expression Supplement
多样性补充:染色质结构和表观遗传变化在砷诱导的基因表达补充中的作用
- 批准号:
9278387 - 财政年份:2016
- 资助金额:
$ 59.27万 - 项目类别:
The role of chromatin structural and epigenetic changes in arsenic-induced gene expression
染色质结构和表观遗传变化在砷诱导的基因表达中的作用
- 批准号:
8887884 - 财政年份:2015
- 资助金额:
$ 59.27万 - 项目类别:
UNDERSTANDING THE MOLECULAR BASIS OF EPIGENETIC TRANSCRIPTIONAL SILENCING
了解表观遗传转录沉默的分子基础
- 批准号:
8360578 - 财政年份:2011
- 资助金额:
$ 59.27万 - 项目类别:
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