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.
Nickel (Ni) compounds, which are environmental pollutants that cause a multitude of health risks in humans, including cancer and cardiovascular diseases, are prevalent in the atmosphere due to the extensive consumption of Ni products and combustion of fossil fuels. Although certain nickel compounds are proven carcinogens, their mutagenic potential is low and the molecular basis of Ni-induced carcinogenicity is not fully understood. In this study, we will investigate how nickel alters the epigenetic landscape resulting in aberrations in gene expression, which may lead to several diseases.
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