Whole-genome DNA methylation analysis of Chinese Hamster Ovary cells undergoing media adaptation

Chinese Hamster Ovary (CHO) cells are widely used for the production of recombinant therapeutics due to their ability to carry out human-like post-translational modifications. Media adaptation represents a key step for large-scale production to ensure optimum safety and cost-efficiency. As DNA methylation is a known epigenetic mechanism in the adaptive modulation of gene expression, we used high-coverage whole-genome bisulfite sequencing to generate single-base resolution maps of CHO cells undergoing different media adaptation protocols. Data analysis of the resulting n=57 high-quality datasets uncovered altered DNA methylation patterns over different phases of growth in a fed-batch culture and in response to different media adaptations. More specifically, we describe how adaptation to 4 different media results in highly specific methylation changes that were associated with distinct functional impacts, including protein productivity. Finally, we introduce a novel platform for streamlined, array-based DNA methylation profiling of CHO cells, which we used to validate key findings from our whole-genome bisulfite sequencing analysis. Our results thus identify and characterize DNA methylation changes during media adaptation and represent a valuable resource for the development of DNA methylation-based biomarkers for the optimisation of CHO cell culture.