Over the last three decades, product yields from CHO cells have increased dramatically, yet specific productivity (qP) remains a limiting factor. In a previous study, using repeated cell-sorting, we have established different host cell subclones that show superior transient qP over their respective parental cell lines (CHO-K1, CHO-S). The transcriptome of the resulting six cell lines in different biological states (untransfected, mock transfected, plasmid transfected) was first explored by hierarchical clustering and indicated that gene activity associated with increased qP did not stem from a certain cellular state but seemed to be inherent for a high qP host line. We then performed a novel gene regression analysis identifying drivers for an increase in qP. Genes significantly implicated were first systematically tested for enrichment of GO terms using a Bayesian approach incorporating the hierarchical structure of the GO term tree. Results indicated that specific cellular components such as nucleus, ER, and Golgi are relevant for cellular productivity. This was complemented by targeted GSA that tested functionally homogeneous, manually curated subsets of KEGG pathways known to be involved in transcription, translation, and protein processing. Significantly implicated pathways included mRNA surveillance, proteasome, protein processing in the ER and SNARE interactions in vesicular transport.
Keywords: Chinese hamster ovary (CHO) productivity; Gene set analysis; Host cell lines; Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways; Microarray profiling.
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