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

Abstract

In eukaryotic cell nuclei, chromatin exhibits a high degree of structural and functional dynamics. Recent findings suggest that chromatin has the ability to reorganize in response to changes within the cellular microenvironment. Such changes include oxidative stress found in hyperoxia. While hyperoxia is recognized for causing DNA damage and disrupting cellular functions, the effects it has on chromatin structure and the implications thereof remain poorly understood. In this work, an imaging-based technique is developed to visualize and characterize nanoscale chromatin remodeling under hyperoxia in mesenchymal stromal cells, created via hydrogen peroxide treatment. High spatiotemporal variability of remodeling in different chromatin domains is found. Chromatin remodeling is hindered by the GSK126-mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Independent assays such as ATAC seq further revealed that chromatin is compacted by hyperoxia, which is mitigated by GSK126 pretreatment. Epigenetic modifications and DNA damage under hyperoxia is investigated, which is also found to be affected by the pretreatment of GSK126. The techniques and discoveries provide mechanistic insights into chromatin remodeling, potentially paving the way for novel therapeutic strategies to combat genotoxic oxidative stress-commonly associated with degenerative diseases and aging-and to enhance cell-based therapies in regenerative medicine.