Epigenetic engineering of ribosomal RNA genes: TIP5 knockdown offers promise for Biopharmaceutical industry

Ribosomal RNA (rRNA) genes code for a major component of ribosomes, a major component in the cell for making proteins. One of the major challenges for the biopharmaceutical manufacturing industry is the selection of mammalian high-producer cell lines. The production of rRNA genes is mainly regulated by the NoRC (Nucleolar remodelling complex) which in turn regulates the cell's full production capacity.

A recent finding by researchers from Switzerland shows that knocking down the TIP5 subunit of NoRC significantly increases the production of recombinant proteins through decrease in number of silent rRNA genes. In their words "... this is the first time that an engineered decrease in the number of silent rRNA genes could be correlated with enhanced production of rRNA and ribosomes and consequently with higher productivity of mammalian cells.". They further state "Epigenetic engineering of ribosomal RNA genes offers new possibilities for improving biopharmaceutical manufacturing and provides novel insights into the complex regulatory network which governs the translation machinery in normal cellular processes as well as in pathological conditions like cancer.".

In a series of experiments, the scientists took an approach to knockdown the expression of TIP5 (TTF-1-interacting protein 5), which is an important component of NoRC. Using the RNA interference technology, the expression of TIP5 was knocked down and followed by examining the levels of rRNA production and ribosome synthesis. To be further sure, a separate experiment showed that enhancement of rRNA transcription rate was not enough to enhance heterlogous protein production.

The results point to a new strategy that could improve biopharmaceutical production of important protein therapeutics. They also provide new possible insights into the complex regulatory networks that govern the translation machinery in a cell.

Their findings appear in the recent issue of PLoS ONE: 4(8): e6653. doi:10.1371/journal.pone.0006653