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

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 pluripote...

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Published in:Nature communications Vol. 9; no. 1; pp. 1261 - 16
Main Authors: Ye, Buqing, Liu, Benyu, Hao, Lu, Zhu, Xiaoxiao, Yang, Liuliu, Wang, Shuo, Xia, Pengyan, Du, Ying, Meng, Shu, Huang, Guanling, Qin, Xiwen, Wang, Yanying, Yan, Xinlong, Li, Chong, Hao, Junfeng, Zhu, Pingping, He, Luyun, Tian, Yong, Fan, Zusen
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 28.03.2018
Nature Publishing Group
Nature Portfolio
Subjects:
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Abnormalities
Animals
Carboxypeptidases - deficiency
Cell Differentiation
Cellular Reprogramming
Clonal deletion
Embryo cells
Embryogenesis
Embryonic growth stage
Embryonic Stem Cells - cytology
Female
Fibroblasts - cytology
Gene Deletion
Gene Expression Regulation, Developmental
Gene Knock-In Techniques
Glutamine - chemistry
HEK293 Cells
Humanities and Social Sciences
Humans
Induced Pluripotent Stem Cells - cytology
KLF4 protein
Kruppel-Like Transcription Factors - metabolism
Lethality
Lysine
Mice
multidisciplinary
Nerve Tissue Proteins - deficiency
Peptide Synthases - metabolism
Peptides - chemistry
Physiological effects
Pluripotency
Science
Science (multidisciplinary)
Stem cell transplantation
Stem cells
Transcription factors
Tubulin
Tyrosine
Ubiquitination
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. Embryonic stem cell pluripotency depends upon precise regulation by a core transcription network. Here the authors show that polyglutamylation mediated stabilization of the transcription factor Klf4 by TTLL1 and TTLL4 promotes reprogramming, pluripotency and preimplantation embryonic development.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-03008-2