Untangling the mechanism of 3-methyladenine in enhancing the specific productivity: Transcriptome analysis of recombinant Chinese hamster ovary cells treated with 3-methyladenine

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3-Methyladenine (3-MA) is a chemical additive that enhances the specific productivity (q(p)) in recombinant Chinese hamster ovary (rCHO) cell lines. Different from its widely known function of inhibiting autophagy, 3-MA has instead shown to increase autophagic flux in various rCHO cell lines. Thus, the mechanism by which 3-MA enhances the q(p) requires investigation. To evaluate the effect of 3-MA on transcriptome dynamics in rCHO cells, RNA-seq was performed with Fc-fusion protein-producing rCHO cells treated with 3-MA. By analyzing genes that were differentially expressed following the addition of 3-MA during culture, the role of 3-MA in the biological processes of rCHO cells was identified. One pathway markedly influenced by the addition of 3-MA was the unfolded protein response (UPR). Having a close relationship with autophagy, the UPR reestablishes protein-folding homeostasis under endoplasmic reticulum (ER) stress. The addition of 3-MA increased the expression of key regulators of the UPR, such as Atf4, Ddit3, and Creb3l3, further supporting the idea that the enhancement of ER capacity acts as a key in increasing the q(p). Consequently, the downstream effectors of UPR, which include autophagy-promoting genes, were upregulated as well. Hence, the role of 3-MA in increasing UPR pathway could have made a salient contribution to the increased autophagic flux in rCHO cells. Taken together, transcriptome analysis improved the understanding of the role of 3-MA in gene expression dynamics in rCHO cells and its mechanism in enhancing the q(p).
Publisher
WILEY
Issue Date
2018-09
Language
English
Article Type
Article
Keywords

UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; CHO-CELLS; ANTIBODY-PRODUCTION; INDUCED APOPTOSIS; MAMMALIAN-CELLS; ER-STRESS; GENE-EXPRESSION; BREAST-CANCER; AUTOPHAGY

Citation

BIOTECHNOLOGY AND BIOENGINEERING, v.115, no.9, pp.2243 - 2254

ISSN
0006-3592
DOI
10.1002/bit.26777
URI
http://hdl.handle.net/10203/245896
Appears in Collection
BS-Journal Papers(저널논문)
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