Pumilio proteins utilize distinct regulatory mechanisms to achieve complementary functions required for pluripotency and embryogenesis.

Autor:	Uyhazi KE; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520., Yang Y; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520.; Shanghai Advanced Institute of Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China., Liu N; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520., Qi H; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520., Huang XA; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520., Mak W; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520.; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06519., Weatherbee SD; Department of Genetics, Yale University School of Medicine, New Haven, CT 06519., de Prisco N; Department of Genetics and Development, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032.; Department of Pediatrics, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032.; Department of Neurology, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032., Gennarino VA; Department of Genetics and Development, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032.; Department of Pediatrics, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032.; Department of Neurology, Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032.; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032., Song X; Shanghai Advanced Institute of Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, China., Lin H; Yale Stem Cell Center, Department of Cell Biology, Yale University, New Haven, CT 06520; haifan.lin@yale.edu.; Shanghai Advanced Institute of Immunochemical Studies, ShanghaiTech University, 201210 Shanghai, China.; School of Life Science and Technology, ShanghaiTech University, 201210 Shanghai, China.; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06519.; Department of Genetics, Yale University School of Medicine, New Haven, CT 06519.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Apr 07; Vol. 117 (14), pp. 7851-7862. Date of Electronic Publication: 2020 Mar 20.
DOI:	10.1073/pnas.1916471117
Abstrakt:	Gene regulation in embryonic stem cells (ESCs) has been extensively studied at the epigenetic-transcriptional level, but not at the posttranscriptional level. Pumilio (Pum) proteins are among the few known translational regulators required for stem-cell maintenance in invertebrates and plants. Here we report the essential function of two murine Pum proteins, Pum1 and Pum2, in ESCs and early embryogenesis. Pum1/2 double-mutant ESCs display severely reduced self-renewal and differentiation, and Pum1/2 double-mutant mice are developmentally delayed at the morula stage and lethal by embryonic day 8.5. Remarkably, Pum1-deficient ESCs show increased expression of pluripotency genes but not differentiation genes, whereas Pum2-deficient ESCs show decreased pluripotency markers and accelerated differentiation. Thus, despite their high homology and overlapping target messenger RNAs (mRNAs), Pum1 promotes differentiation while Pum2 promotes self-renewal in ESCs. Pum1 and Pum2 achieve these two complementary aspects of pluripotency by forming a negative interregulatory feedback loop that directly regulates at least 1,486 mRNAs. Pum1 and Pum2 regulate target mRNAs not only by repressing translation, but also by promoting translation and enhancing or reducing mRNA stability of different target mRNAs. Together, these findings reveal distinct roles of individual mammalian Pum proteins in ESCs and their essential functions in ESC pluripotency and embryogenesis. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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