Klf4 glutamylation is required for cell reprogramming and early embryonic development in mice

Buqing Ye, Benyu Liu, Lu Hao, Xiaoxiao Zhu, Liuliu Yang, Shuo Wang, Pengyan Xia, Ying Du, Shu Meng, Guanling Huang, Xiwen Qin, Yanying Wang, Xinlong Yan, Chong Li, Junfeng Hao, Pingping Zhu, Luyun He, Yong Tian () and Zusen Fan ()
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Buqing Ye: Chinese Academy of Sciences
Benyu Liu: Chinese Academy of Sciences
Lu Hao: Chinese Academy of Sciences
Xiaoxiao Zhu: Chinese Academy of Sciences
Liuliu Yang: Chinese Academy of Sciences
Shuo Wang: Chinese Academy of Sciences
Pengyan Xia: Chinese Academy of Sciences
Ying Du: Chinese Academy of Sciences
Shu Meng: Chinese Academy of Sciences
Guanling Huang: Chinese Academy of Sciences
Xiwen Qin: Chinese Academy of Sciences
Yanying Wang: Chinese Academy of Sciences
Xinlong Yan: Chinese Academy of Sciences
Chong Li: Chinese Academy of Sciences
Junfeng Hao: Chinese Academy of Sciences
Pingping Zhu: Chinese Academy of Sciences
Luyun He: Chinese Academy of Sciences
Yong Tian: Chinese Academy of Sciences
Zusen Fan: Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. Misregulation of glutamylation is implicated in severe physiological abnormalities. However, how glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Here we show that cytosolic carboxypeptidases 1 (CCP1) or CCP6 deficiency substantially promotes induced pluripotent cell (iPSC) induction and pluripotency of embryonic stem cells (ESCs). Klf4 polyglutamylation at Glu381 by tubulin tyrosine ligase-like 4 (TTLL4) and TTLL1 during cell reprogramming impedes its lysine 48-linked ubiquitination and sustains Klf4 stability. Klf4-E381A knockin mice display impaired blastocyst development and embryonic lethality. Deletion of TTLL4 or TTLL1 abrogates cell reprogramming and early embryogenesis. Thus, Klf4 polyglutamylation plays a critical role in the regulation of cell reprogramming and pluripotency maintenance.

Date: 2018
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DOI: 10.1038/s41467-018-03008-2

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