Hyperoxia Induced Alteration of Chromatin Structure in Bone Marrow Derived Primary Mesenchymal Stromal Cells

ABSTRACT Chromatin is a highly dynamic entity of the eukaryotic cell nucleus. New evidence is emerging in support of the notion that chromatin can locally and globally rearrange itself to adapt with the cellular microenvironmental changes. Such changes include oxidative stress such as supraphysiological oxygen level, found in hyperoxia. Although it is known that hyperoxia can result in DNA damage and alterations in cell function, it is not well understood how the chromatin architecture changes under such a condition and what the functional significance of such change entails. In this work we developed an imaging-based technique to visualize and characterize nanoscale chromatin remodeling under hyperoxia, created via hydrogen peroxide treatment. We found high spatiotemporal variability of remodeling in different chromatin domains such as the euchromatin, heterochromatin and interchromatin. Chromatin remodeling was hindered by the GSK126 mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Epigenetic modifications and DNA damage under hyperoxia was investigated, which was found affected by the pretreatment of GSK126. The developed techniques and findings inform us with new mechanistic insights of chromatin remodeling which might lead to new intervention strategies to target genotoxic hyper-oxidative stress, which is common in degenerative diseases and aging, and for cell therapy in regenerative medicine.