Addition of a histone deacetylase inhibitor increases recombinant protein expression in plant cell cultures

Plant cell cultures are an attractive platform for the production of complex recombinant proteins, with lower costs than mammalian cells. A major drawback, hindering the establishment of plant cell suspensions as an industrial platform, is the low yields obtained thus far. Histone acetylation is associated with increased transcription levels. It is expected that the use of histone deacetylase inhibitors (HDACi) would result in an increase in mRNA and protein levels. This hypothesis was tested by adding HDACi to a cell line of the model legume Medicago truncatula expressing a recombinant human protein. Histone deacetylase inhibition and histone H3 acetylation levels were studied, and the effect of HDACi on gene expression and recombinant protein levels was assessed by digital PCR. HDACi were able to inhibit histone deacetylase activity resulting in increased histone H3 acetylation. Higher levels of transgene expression and protein accumulation were observed. This is the first report describing HDACi as inducers of recombinant protein expression in plant cell suspensions as well as the use of digital PCR in these biological systems. This study paves the way for employing epigenetic strategies to improve the final yields of recombinant proteins produced by plant cell cultures.