title: Epigenetic engineering of ribosomal RNA genes enhances protein production.
abstract: Selection of mammalian high-producer cell lines remains a major challenge for the biopharmaceutical manufacturing industry. Ribosomal RNA (rRNA) genes encode the major component of the ribosome but many rRNA gene copies are not transcribed due to epigenetic silencing by the nucleolar remodelling complex (NoRC) [6], which may limit the cell's full production capacity. Here we show that the knockdown of TIP5, a subunit of NoRC, decreases the number of silent rRNA genes, upregulates rRNA transcription, enhances ribosome synthesis and increases production of recombinant proteins. However, general enhancement of rRNA transcription rate did not stimulate protein synthesis. Our data demonstrates that the number of transcriptionally competent rRNA genes limits efficient ribosome synthesis. 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.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland. raffaella.santoro@bsse.ethz.ch
authors.forename: Raffaella
authors.initials: R
authors.lastname: Santoro
authors.forename: Philipp
authors.initials: P
authors.lastname: Lienemann
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D016475:3T3 Cells; D000818:Animals; D016466:CHO Cells; D018899:CpG Islands; D006224:Cricetinae; D003412:Cricetulus; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D018628:Gene Dosage; D020868:Gene Silencing; D005818:Genetic Engineering; D051379:Mice; D014176:Protein Biosynthesis; D012335:RNA, Ribosomal / Q000235:genetics*; D015854:Up-Regulation
chemical_list: D012335:RNA, Ribosomal
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