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.
Highlights
Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors
We noticed that CCP6 deficiency caused higher litter size at birth (Supplementary Figure 1a), whereas Ccp6-deficient mice displayed similar sperm and ovulation numbers compared with littermate control mice, suggesting CCP6 could be implicated in the modulation of cellular reprogramming
To determine whether glutamylation is involved in somatic cell reprogramming, we first generated Ccp1−/−, or Ccp6−/− mouse embryonic fibroblasts (MEFs) (Fig. 1a), and transduced Yamanaka factors OSKM for induced pluripotent stem cells (iPSCs) induction assays
Summary
Temporal and spatial-specific regulation of pluripotency networks is largely dependent on the precise modifications of core transcription factors. How glutamylation regulates cell reprogramming and pluripotency networks remains elusive. Klf[4] polyglutamylation plays a critical role in the regulation of cell reprogramming and pluripotency maintenance. The temporal and spatial-specific regulation of pluripotency networks largely depends on precise modifications and interaction controls of the core transcriptional factors[6,7,8,9]. These reprogramming factors are highly modified post-transcriptionally at the levels of mRNA stability, translation and protein activity[7,10]. How glutamylation regulates cell reprogramming and pluripotency maintenance remains elusive
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