Iron Oxide Nanoparticles with and without Cobalt Functionalization Provoke Changes in the Transcription Profile via Epigenetic Modulation of Enhancer Activity

Despite the progress in the field of nanotoxicology,much aboutthe cellular mechanisms that mediate the adverse effects of nanoparticles(NPs) and, in particular, the possible role of epigenetics in nanotoxicity,remains to be clarified. Therefore, we studied the changes occurringin the genome-wide distribution of H3K27ac, H3K4me1, H3K9me2, andH3K27me3 histone modifications and compared them with the transcriptomeafter exposing NIH3T3 cells to iron-based magnetic NPs (i.e., Fe2O3 and Fe2O3@Co NPs). Wefound that the transcription response is mainly due to changes inthe genomic distribution of H3K27ac that can modulate the activityof enhancers. We propose that alteration of the epigenetic landscapeis a key mechanism in defining the gene expression program changesresulting in nanotoxicity. With this approach, it is possible to constructa data set of genomic regions that could be useful for defining toxicityin a manner that is more comprehensive than what is possible withthe present toxicology assays.

Automated summary

Despite the progress in nanotoxicology, the cellular mechanisms of nanoparticles' adverse effects and the role of epigenetics in nanotoxicity remain unclear. This study investigated changes in histone modifications and transcriptome after exposing NIH3T3 cells to iron-based magnetic NPs. The results suggest that alterations in the epigenetic landscape play a key role in defining gene expression changes and nanotoxicity.