Epigenetic regulation of gene expression in Chinese hamster ovary cells in response to the changing environment of a batch culture

Hernandez, Inmaculada; Dhiman, Heena; Klanert, Gerald; Jadhav, Vaibhav; Auer, Norbert; Hanscho, Michael; Baumann, Martina; Esteve-Codina, Anna; Dabad, Marc; Gómez, Jessica; Alioto, Tyler; Merkel, Angelika; Raineri, Emanuele; Heath, Simon; Rico, Daniel; Borth, Nicole

Epigenetic regulation of gene expression in Chinese hamster ovary cells in response to the changing environment of a batch culture

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dc.contributor.author Hernandez, Inmaculada
dc.contributor.author Dhiman, Heena
dc.contributor.author Klanert, Gerald
dc.contributor.author Jadhav, Vaibhav
dc.contributor.author Auer, Norbert
dc.contributor.author Hanscho, Michael
dc.contributor.author Baumann, Martina
dc.contributor.author Esteve-Codina, Anna
dc.contributor.author Dabad, Marc
dc.contributor.author Gómez, Jessica
dc.contributor.author Alioto, Tyler
dc.contributor.author Merkel, Angelika
dc.contributor.author Raineri, Emanuele
dc.contributor.author Heath, Simon
dc.contributor.author Rico, Daniel
dc.contributor.author Borth, Nicole
dc.date.accessioned 2022-04-25T12:28:23Z
dc.date.available 2022-04-25T12:28:23Z
dc.date.issued 2019
dc.description.abstract The existence of dynamic cellular phenotypes in changing environmental conditions is of major interest for cell biologists who aim to understand the mechanism and sequence of regulation of gene expression. In the context of therapeutic protein production by Chinese Hamster Ovary (CHO) cells, a detailed temporal understanding of cell-line behavior and control is necessary to achieve a more predictable and reliable process performance. Of particular interest are data on dynamic, temporally resolved transcriptional regulation of genes in response to altered substrate availability and culture conditions. In this study, the gene transcription dynamics throughout a 9-day batch culture of CHO cells was examined by analyzing histone modifications and gene expression profiles in regular 12- and 24-hr intervals, respectively. Three levels of regulation were observed: (a) the presence or absence of DNA methylation in the promoter region provides an ON/OFF switch; (b) a temporally resolved correlation is observed between the presence of active transcription- and promoter-specific histone marks and the expression level of the respective genes; and (c) a major mechanism of gene regulation is identified by interaction of coding genes with long non-coding RNA (lncRNA), as observed in the regulation of the expression level of both neighboring coding/lnc gene pairs and of gene pairs where the lncRNA is able to form RNA-DNA-DNA triplexes. Such triplex-forming regions were predominantly found in the promoter or enhancer region of the targeted coding gene. Significantly, the coding genes with the highest degree of variation in expression during the batch culture are characterized by a larger number of possible triplex-forming interactions with differentially expressed lncRNAs. This indicates a specific role of lncRNA-triplexes in enabling rapid and large changes in transcription. A more comprehensive understanding of these regulatory mechanisms will provide an opportunity for new tools to control cellular behavior and to engineer enhanced phenotypes.
dc.description.sponsorship Funding: IHL received support from FWF, the Austrian Science Fund, within the Doctoral Program “BioTechnology of Proteins” W1224, and HD from the “eCHO Systems” ITN PhD program funded by the Marie Sklodowska-Curie grant no. 642663. Additional grants were received from the National Bioinformatics Institute (INB), PRB2-ISCIII (PT13/0001/0044 to JG and AEC) and MINECO (PTA2014-09515 to MD)
dc.format.mimetype application/pdf
dc.identifier.citation Hernandez I, Dhiman H, Klanert G, Jadhav V, Auer N, Hanscho M et al. Epigenetic regulation of gene expression in Chinese hamster ovary cells in response to the changing environment of a batch culture. Biotechnol Bioeng. 2019 Mar;116(3):677-692. DOI:10.1002/bit.26891
dc.identifier.doi http://dx.doi.org/10.1002/bit.26891
dc.identifier.issn 0006-3592
dc.identifier.uri http://hdl.handle.net/10230/52887
dc.language.iso eng
dc.publisher Wiley
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/642663
dc.rights © 2019 Inmaculada Hernandez et al. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.other Epigenètica
dc.subject.other Expressió gènica
dc.subject.other Ovaris
dc.title Epigenetic regulation of gene expression in Chinese hamster ovary cells in response to the changing environment of a batch culture
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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