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Reprogramming Mouse Embryonic Fibroblasts with Transcription Factors to Induce a Hemogenic Program
Published on: December 16, 2016
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Klf4 glutamylation is required for cell reprogramming and early embryonic development in mice
Buqing Ye1, Benyu Liu1, Lu Hao1,2
1Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
Nature Communications
|March 30, 2018
Summary
Cytosolic carboxypeptidase deficiency enhances induced pluripotent stem cell (iPSC) generation. Klf4 polyglutamylation by TTLL4/TTLL1 stabilizes Klf4, crucial for pluripotency and embryonic development.
Area of Science:
- Cellular biology
- Developmental biology
- Epigenetics
Background:
- Precise modification of transcription factors is key for pluripotency network regulation.
- Glutamylation misregulation is linked to physiological abnormalities, but its role in cell reprogramming is unclear.
Purpose of the Study:
- To investigate the role of glutamylation in regulating cell reprogramming and pluripotency networks.
- To elucidate the mechanism by which glutamylation impacts key pluripotency factors like Klf4.
Main Methods:
- Utilized knockout models for cytosolic carboxypeptidases (CCP1, CCP6) and glutamylases (TTLL4, TTLL1).
- Generated Klf4-E381A knockin mice to assess the functional impact of specific glutamylation.
- Analyzed induced pluripotent stem cell (iPSC) induction efficiency and embryonic stem cell (ESC) pluripotency.
Main Results:
- Deficiency in CCP1 or CCP6 significantly promoted iPSC induction and ESC pluripotency.
- Klf4 polyglutamylation at Glu381 by TTLL4 and TTLL1 was shown to inhibit Klf4 ubiquitination, enhancing its stability.
- Klf4-E381A knockin mice exhibited developmental defects, including impaired blastocyst development and embryonic lethality.
- Deletion of TTLL4 or TTLL1 disrupted cell reprogramming and early embryogenesis.
Conclusions:
- Klf4 polyglutamylation is a critical regulatory mechanism for cell reprogramming and pluripotency maintenance.
- The TTLL4/TTLL1-mediated glutamylation pathway stabilizes Klf4, essential for embryonic development and stem cell biology.
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