title: Overexpression of YY1 increases the protein production in mammalian cells.
abstract: The production of therapeutic antibodies using mammalian cells remains a high-priority in the biopharmaceutical manufacturing industry. Bioengineers have targeted different cellular processes, including transcription, translation, secretion and post-translational modifications, to overcome the metabolic bottlenecks limiting production capacity and create high-producing mammalian cell lines. The polycomb group (PcG) proteins belong to a family of chromatin regulators with important roles in multicellular development. By overexpressing and screening genes from the PcG family, we have identified an epigenetic key player for biopharmaceutical manufacturing enhancement: the transcription factor Yin Yang 1 (YY1). The overexpression of YY1 led to an increase in the production of several product genes (SEAP, VEGF165, IgG including Rituximab), provided that human YY1 (hYY1) was expressed in human cells (HeLa, HT-1080, HEK-293T, FreeStyle™ 293-F) and Chinese hamster ovary cell-derived YY1 (cYY1) was expressed in CHO cells (CHO-K1, CHO-easyC, FreeStyle™ CHO-S, CHO-B13-24, CHO-IgG1). Ectopic expression of cYY1 in the stable CHO-derived IgG producer cell lines CHO-B13-24 and CHO-IgG1 increased the antibody titer up to 6-fold, suggesting that epigenetic engineering of mammalian production cell lines could become a new strategy to improve the manufacturing of complex protein pharmaceuticals.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Aizhan
authors.initials: A
authors.lastname: Tastanova
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Marc
authors.initials: M
authors.lastname: Folcher
authors.affiliation: Biogen, Biogen Idec Allé 1, DK-3400 Hilleroed, Denmark.
authors.forename: Anne
authors.initials: A
authors.lastname: Tolstrup
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Process Science, Birkendorfer Strasse 65, D-88397 Biberach, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Puklowski
authors.affiliation: Sanofi, Sanofi Biologics, Industriepark Hoechst, D-65926 Frankfurt am Main, Germany.
authors.forename: Hitto
authors.initials: H
authors.lastname: Kaufmann
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland; Faculty of Science, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland. Electronic address: fussenegger@bsse.ethz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D015202:Protein Engineering / Q000379:methods*; D050986:YY1 Transcription Factor / Q000235:genetics*
chemical_list: D000906:Antibodies; D050986:YY1 Transcription Factor; C494698:YY1 protein, human
keywords: Biopharmaceutical manufacturing; Chinese hamster overy cells; Epigenеtics; Metabolic engineering; Rituximab