Epigenetic reprogramming by nickel through chromatin domain disruption

 描述(申请人提供)：由于镍产品的广泛消费和化石燃料的燃烧，镍(镍)化合物在大气中很普遍。镍化合物是一种环境污染物，会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。虽然镍是一种已被证实的致癌物，但其诱变潜力很低，而且镍诱导致癌的分子基础还不完全清楚。新出现的证据表明，镍以及其他环境污染物，如砷和镉，可以通过染色质修饰的失调导致癌症和其他疾病的发生，包括DNA甲基化和组蛋白的翻译后修饰。因此，了解环境污染物破坏染色质修饰的潜在机制是至关重要的。我们对镍暴露细胞中几种组蛋白修饰的全基因组分析显示，异染色质标记，组蛋白H3赖氨酸9二甲基化(H3K9me2)发生了显著变化。H3K9me2标记了基因组的大片连续区域，形成了抑制染色质结构域。镍暴露引起H3K9me2结构域的破坏并扩散到活动区，这与转录抑制相对应。有趣的是，我们发现绝缘蛋白CCCTCC结合因子(CTCF)的DNA结合在镍破坏的结构域界面上较弱，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，镍还抑制Jumonji C(JmjC)结构域H3K9me2去甲基酶的活性。去甲基酶对于维持H3K9me2的稳定水平很重要，它们的失活可能会导致H3K9me2的传播。这些结果表明，在镍诱导的基因表达改变中，染色质结构域维持的中断是重要的。我们假设，镍干扰染色质结构域的维持，导致高阶染色质结构的持续变化，并导致异常转录调节。在这项研究中，我们将调查染色质结构域中断的原因以及由此导致的转录程序的改变。这个项目的最终目标是描述 基于表观遗传失调的环境诱发疾病的新机制。这项研究的结果将对治疗开发具有重要意义，因为表观遗传修饰是动态和可逆的，因此是有吸引力的药物靶点。

 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.