Epigenetic reprogramming by nickel through chromatin domain disruption

镍通过染色质结构域破坏进行表观遗传重编程

• 批准号: 9137673
• 负责人: Suresh Cuddapah
• 金额: $ 38.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137673
• 关键词: Arsenic; Atopic Dermatitis; Binding; Binding Sites; Cadmium; Carcinogens; Cardiovascular Diseases; Cell Culture Techniques; Cells; ChIP-seq; Chloride Ion; Chlorides; Chromatin; Consumption; DNA Binding; DNA Methylation; Data; Development; Disease; Drug Targeting; Environmental Pollutants; Epigenetic Process; Epithelial; Epithelial Cells; Exposure to; Fossil Fuels; Gene Expression; Gene Expression Alteration; Gene Silencing; Generations; Genome; Goals; Health; Heterochromatin; Higher Order Chromatin Structure; Histone H3; Histones; Human; Lead; Lung; Lysine; Maintenance; Malignant Neoplasms; Maps; Modification; Molecular; Nickel; Nickel Subsulfide; Nose; Particulate; Population; Post-Translational Protein Processing; Proteins; RNA; Risk; Risk Factors; Role; Toxic Environmental Substances; Transcriptional Regulation; base; carcinogenicity; chromatin modification; combustion product; epigenetic memory; functional outcomes; gene repression; genome analysis; genome-wide; histone modification; in vivo; knock-down; novel; overexpression; planetary Atmosphere; prevent; programs; promoter; therapeutic development; transcription factor; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): Nickel (Ni) compounds are prevalent in the atmosphere due to the extensive consumption of Ni products and combustion of fossil fuels. Ni compounds are environmental pollutants that cause a multitude of health risks in humans, including lung and nasal cancers, cardiovascular diseases as well as allergic dermatitis. Although Ni is a proven carcinogen, its mutagenic potential is low and the molecular basis of Ni-induced carcinogenicity is not fully understood. Emerging evidence suggests that Ni as well as other environmental pollutants such as arsenic and cadmium can induce development of cancer and other diseases through the dysregulation of chromatin modifications, including DNA methylation and post-translational modifications to histone proteins. It is therefore of fundamental importance to understand the mechanisms underlying disruption of chromatin modifications by environmental pollutants. Our whole genome analysis of several histone modifications in Ni- exposed cells revealed significant alterations in the heterochromatin mark, histone H3 lysine 9 dimethylation (H3K9me2). H3K9me2 marked large contiguous regions of the genome, forming repressive chromatin domains. Ni-exposure caused H3K9me2 domain disruption and spreading into active regions, which corresponded with transcriptional repression. Interestingly, we found that the DNA binding of the insulator protein CCCTCC-binding factor (CTCF) was weaker at Ni-disrupted domain boundaries, suggesting loss of CTCF binding as a potential reason for H3K9me2 domain disruption in Ni-exposed cells. In addition, Ni inhibits the activity of the Jumonji C (JmjC) domain H3K9me2 demethylases. The demethylases are important for maintaining steady-state levels of H3K9me2 and their inactivation could potentially contribute to H3K9me2 spreading. These results suggest disruption in chromatin domain maintenance to be important in Ni-induced gene expression alterations. We hypothesize that Ni interferes with the chromatin domain maintenance leading to persistent alterations to the higher order chromatin structure and resulting in aberrant transcriptional regulation. In this study, we will investigate the causes for chromatin domain disruption and the resultant alterations to the transcriptional program. The end goal of this project is the characterization of novel mechanisms for environmental induced disease based on epigenetic dysregulation. The results from this study will be important for therapeutic development given that epigenetic modifications are dynamic and reversible, thus being attractive drug targets.

 描述（由申请人提供）：由于镍产品的大量消耗和化石燃料的燃烧，镍（Ni）化合物在大气中普遍存在。镍化合物是环境污染物，对人类造成多种健康风险，包括肺癌和鼻癌、心血管疾病以及过敏性皮炎。虽然镍是一种已证实的致癌物，但其致突变潜力较低，镍诱导致癌性的分子基础尚未完全了解。新出现的证据表明，镍以及砷和镉等其他环境污染物可以通过染色质修饰的失调（包括DNA甲基化和组蛋白的翻译后修饰）诱导癌症和其他疾病的发展。因此，了解环境污染物破坏染色质修饰的机制具有根本的重要性。我们对镍暴露细胞中几种组蛋白修饰的全基因组分析揭示了异染色质标记，组蛋白H3赖氨酸9二甲基化（H3K9me2）的显著改变。H3 K9 me2标记基因组的大片连续区域，形成抑制性染色质结构域。镍暴露导致H3K9me2结构域破坏并扩散到活性区域，这与转录抑制相对应。有趣的是，我们发现绝缘子蛋白CCCTCC结合因子（CTCF）的DNA结合在镍破坏的结构域边界处较弱，这表明CTCF结合的丧失是镍暴露细胞中H3K9me2结构域破坏的潜在原因。此外，Ni抑制Jumonji C（JmjC）结构域H3K9me2脱甲基酶的活性。脱甲基酶对于维持H3K9me2的稳态水平是重要的，并且它们的失活可能有助于H3K9me2的扩散。这些结果表明，染色质结构域的维护中断是重要的镍诱导的基因表达改变。我们推测，镍干扰染色质结构域的维护，导致持久的改变，以更高的顺序染色质结构，并导致异常的转录调控。在这项研究中，我们将调查的原因染色质结构域中断和由此产生的改变的转录程序。该项目的最终目标是描述 基于表观遗传失调的环境诱导疾病的新机制。鉴于表观遗传修饰是动态的和可逆的，因此是有吸引力的药物靶点，这项研究的结果对于治疗开发将是重要的。