Chromatin assembly and formaldehyde toxicity

染色质组装和甲醛毒性

• 批准号: 10443076
• 负责人: Chunyuan Jin
• 金额: $ 55.69万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10443076
• 关键词: Acetylation; Affect; Biological Assay; Bone Marrow; Cell physiology; Cells; ChIP-seq; Chemicals; Chromatin; Chromatin Modeling; Chromatin Structure; Chromosomal Instability; Cytoplasm; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA-protein crosslink; Data; Defect; Deposition; Environment; Epigenetic Process; Exposure to; Formaldehyde; Fractionation; Gene Abnormality; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genome Stability; Genomic Instability; Histone H3; Histone H4; Histones; Household Products; Impairment; In Vitro; Industrialization; Link; Location; Lysine; Malignant Neoplasms; Malignant neoplasm of nasopharynx; Maps; Modification; Molecular; Molecular Chaperones; Monitor; Mutagenesis; Mutate; Myeloid Leukemia; Nuclear Import; Occupational; Occupations; Peptides; Post-Translational Protein Processing; Process; Proteins; Proteomics; Rattus; Refractory; Research; Role; Schiff Bases; Site; Structure of mucous membrane of nose; Structure of parenchyma of lung; System; Testing; Tissues; Toxic effect; Variant; Western Blotting; adduct; base; building materials; cancer type; carcinogenesis; carcinogenicity; chemical carcinogen; chemical carcinogenesis; chromatin immunoprecipitation; exposed human population; genomic locus; histone modification; human disease; in vivo; inducible gene expression; innovation; knock-down; live cell imaging; novel; overexpression; toxicant; trafficking

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.

项目概要 甲醛是一种已知的环境和职业化学致癌物质。的分子机制 甲醛诱发的致癌作用在很大程度上尚未确定。 DNA损伤及其相关 DNA加合物和DNA-蛋白质交联诱导的诱变一直是甲醛研究的焦点 致癌性研究。然而，最近的研究表明，外源性甲醛仅导致 DNA 加合物适度增加至高于内源性甲醛引起的水平。这建议了 表观遗传机制可能导致甲醛诱发的致癌性。我们和 其他人已经证明甲醛与组蛋白上的赖氨酸残基反应形成不稳定的 希夫碱或更稳定的 N6-甲酰赖氨酸，并且希夫碱和 N6-甲酰赖氨酸残基都是 难于乙酰化。这些发现表明甲醛-组蛋白赖氨酸加合物可能会干扰 组蛋白赖氨酸乙酰化调节的重要细胞过程。但目前尚不清楚是哪个过程 受此机制影响。我们来自细胞分级分析的初步数据表明 甲醛暴露显着降低胞质组蛋白 H3 和 H4 的赖氨酸乙酰化。这 鉴于这些修饰对于组蛋白核输入和染色质至关重要，这一发现非常有趣 集会。我们的初步结果进一步表明，甲醛降低了组蛋白的总量 染色质分数和基因组位点的组蛋白水平，表明染色质组装受到抑制。 有缺陷的染色质组装会导致基因表达失调和基因组不稳定， 与不同类型的癌症直接相关。基于这些观察，我们假设形成 甲醛-组蛋白加合物会损害组蛋白核输入和/或染色质组装，从而 促进甲醛诱发的致癌作用。为了检验这个假设，在目标 1 中，我们将检验 新合成的组蛋白的核输入及其组装成染色质是否受到损害 甲醛暴露后并确定潜在机制。在目标 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、形成 DNA 加合物和 DNA-蛋白质交联，以及染色体不稳定性。在目标 3 中，我们将调查是否 甲醛暴露会损害体内染色质组装。所提出的概念是化学物质 致癌物与新合成的组蛋白反应来调节染色质组装是新颖的。这项研究有 有望揭示化学致癌的新机制。