Pioneer factor FOXA1 can boost CHO cell productivity

Abstract

Industrial production of biologics commonly involves the integration of transgenes into genomes of host cells, such as Chinese hamster ovary (CHO) cells. A major determinant of productivity is the epigenetic control of the transgene promoter, accessibility of which can decrease during production due to the spread of heterochromatin. Pioneer factors such as forkhead box A1 (FOXA1) can bind heterochromatin, increase its accessibility and facilitate transcription of target genes. We show that FOXA1 can bind the EF1 promoter, which is widely used in industry. Overexpressing FOXA1 in an industrially-relevant CHO-DG44 cell line raised production of monoclonal antibody encoded by transgenes transcribed from EF1 promoters. Mechanistically, this response can be attributed to recruitment by FOXA1 of epigenetic modifiers and a chromatin remodelling complex, which reprogramme the promoter to optimise transcription. In parallel, FOXA1 overexpression induces endogenous genes with beneficial effects on cell viability. This strategy significantly enhanced cell-specific productivity, demonstrating potential benefit in biomanufacturing.