Chromatin assembly and formaldehyde toxicity
染色质组装和甲醛毒性
基本信息
- 批准号:10597201
- 负责人:
- 金额:$ 54.26万
- 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:2022-03-25 至 2026-12-31
- 项目状态:未结题
- 来源:
- 关键词:AcetylationAffectBiological AssayBone MarrowCell physiologyCellsChIP-seqChemicalsChromatinChromatin ModelingChromatin StructureChromosomal InstabilityCytoplasmDNA AdductionDNA AdductsDNA DamageDNA RepairDNA-protein crosslinkDataDefectDepositionEnvironmentEpigenetic ProcessFormaldehydeFractionationGene AbnormalityGene ExpressionGenesGeneticGenetic TranscriptionGenomeGenome StabilityGenomic InstabilityHistone H3Histone H4HistonesHousehold ProductsImpairmentIn VitroIndustrializationLinkLocationLysineMalignant NeoplasmsMalignant neoplasm of nasopharynxMapsModificationMolecularMolecular ChaperonesMonitorMutagenesisMutateMyeloid LeukemiaNuclear ImportOccupationalOccupationsPeptidesPost-Translational Protein ProcessingProcessProteinsProteomicsRattusReactionRefractoryResearchRoleSchiff BasesSiteStructure of mucous membrane of noseStructure of parenchyma of lungSystemTestingTissuesToxic effectVariantWestern Blottingadductbuilding materialscancer typecarcinogenesiscarcinogenicitychemical carcinogenchemical carcinogenesischromatin immunoprecipitationexposed human populationgenomic locushistone modificationhuman diseasein vivoinducible gene expressioninnovationknock-downlive cell imagingnoveloverexpressiontoxicanttrafficking
项目摘要
PROJECT SUMMARY
Formaldehyde is a known environmental and occupational chemical carcinogen. The molecular mechanisms of
formaldehyde-induced carcinogenesis are largely undetermined. The DNA damage and associated
mutagenesis induced by DNA adducts and DNA-protein crosslinks have been the focus of formaldehyde
carcinogenicity research. However, recent studies showed that exogenous formaldehyde caused only a
modest increase in DNA adducts above levels caused by endogenous formaldehyde. This suggested the
possibility that epigenetic mechanisms might contribute to formaldehyde-induced carcinogenicity. We and
others have demonstrated that formaldehyde reacts with lysine residues on histone proteins to form a labile
Schiff base or the more stable N6-formyllysine, and that both Schiff bases and N6-formyllysine residues are
refractory to acetylation. These findings indicated that formaldehyde-histone lysine adducts might interfere with
important cellular process regulated by histone lysine acetylation. However, it remains unknown which process
is affected by this mechanism. Our preliminary data from cellular fractionation analyses demonstrate that
formaldehyde exposure dramatically decreases lysine acetylations of the cytosolic histones H3 and H4. This
finding is very intriguing, given that these modifications are critical for histone nuclear import and chromatin
assembly. Our preliminary results further show that formaldehyde reduces the total amount of histone in the
chromatin fraction and the levels of histones at genomic loci, suggesting inhibition of chromatin assembly.
Defective chromatin assembly causes dysregulation of gene expression and genomic instability and was
directly linked to different types of cancers. Based on these observations, we hypothesize that the formation of
formaldehyde-histone adducts compromises histone nuclear import and/or chromatin assembly, thereby
contributing to formaldehyde-induced carcinogenesis. To test this hypothesis, in Aim 1, we will examine
whether the nuclear import of newly synthesized histones and their assembly into chromatin are compromised
following formaldehyde exposure and determine the underlying mechanisms. In Aim 2, we will determine the
impact of aberrant chromatin assembly on formaldehyde-induced changes in gene expression, formation of
DNA adducts and DNA-protein crosslinks, and chromosome instability. In Aim 3, we will investigate whether
formaldehyde exposure compromises chromatin assembly in vivo. The proposed concept that a chemical
carcinogen reacts with newly synthesized histones to regulate chromatin assembly is novel. This study has the
potential to reveal a new mechanism for chemical carcinogenesis.
项目摘要
甲醛是已知的环境和职业化学致癌。分子机制
甲醛诱导的致癌作用在很大程度上尚未确定。 DNA损伤和相关
DNA加合物和DNA-蛋白交联引起的诱变已成为甲醛的重点
致癌性研究。然而,最近的研究表明,外源甲醛仅引起
由内源性甲醛引起的高于水平的DNA加合物的适度增加。这暗示了
表观遗传机制可能有助于甲醛诱导的致癌性。我们和
其他人证明甲醛与组蛋白上的赖氨酸残基反应形成不稳定的
Schiff碱或更稳定的N6-甲酰胺,并且Schiff碱和N6-甲基透析残基是
对乙酰化的难治。这些发现表明,甲醛 - 甲醛赖氨酸加合物可能会干扰
由组蛋白赖氨酸乙酰化调节的重要细胞过程。但是,尚不清楚哪个过程
受这种机制的影响。我们来自细胞分级分析的初步数据表明,
甲醛暴露大大降低了胞质组蛋白H3和H4的赖氨酸乙酰化。这
鉴于这些修饰对于组蛋白核进口和染色质至关重要,发现很有趣
集会。我们的初步结果进一步表明,甲醛减少了组蛋白的总量
染色质馏分和基因组基因座的组蛋白水平,表明抑制染色质组装。
染色质组装有缺陷会导致基因表达和基因组不稳定性的失调,并且
直接链接到不同类型的癌症。基于这些观察,我们假设
甲醛 - 甲酮加合物损害了组蛋白的核进口和/或染色质组装,从而损害了
有助于甲醛诱导的癌变。为了检验这一假设,在AIM 1中,我们将研究
新合成的组蛋白及其组装到染色质中的核进口是否受到损害
甲醛暴露并确定基本机制。在AIM 2中,我们将确定
异常染色质组装对甲醛诱导的基因表达变化的影响,形成
DNA加合物和DNA-蛋白交联,染色体不稳定性。在AIM 3中,我们将调查是否
甲醛暴露会损害体内染色质组装。提出的概念是一种化学的概念
致癌物与新合成的组蛋白反应以调节染色质组装是新颖的。这项研究有
揭示新的化学癌变机制的潜力。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Chunyuan Jin其他文献
Chunyuan Jin的其他文献
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