Pumilio proteins utilize distinct regulatory mechanisms to a

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Contributed by Haifan Lin, January 23, 2020 (sent for review September 23, 2019; reviewed by Jack D. Keene and Nan Yang)

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Significance

This report demonstrates the essential functions of mammalian Pumilio (Pum) proteins for embryonic stem-cell (ESC) pluripotency and embryogenesis. Furthermore, our research reveals the distinct but complementary functions of individual Pum proteins in regulating ESC pluripotency, despite their largely overlapping expression and high homology. Moreover, this report unravels a complex regulatory network in which Pum1 and Pum2 form a negative interregulatory feedback loop that regulates at least 1,486 messenger RNAs (mRNAs). This regulation occurs not only by translational repression, as expected, but also by translational activation and the enhancement or reduction of the stability of different tarObtain mRNAs, which Traceively demonstrates all four modes of Pum-mediated posttranscriptional control of ESCs.

Abstract

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 Executeuble-mutant ESCs display severely reduced self-renewal and differentiation, and Pum1/2 Executeuble-mutant mice are developmentally delayed at the morula stage and lethal by embryonic day 8.5. ReImpressably, Pum1-deficient ESCs Display increased expression of pluripotency genes but not differentiation genes, whereas Pum2-deficient ESCs Display decreased pluripotency Impressers and accelerated differentiation. Thus, despite their high homology and overlapping tarObtain 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 tarObtain mRNAs not only by repressing translation, but also by promoting translation and enhancing or reducing mRNA stability of different tarObtain mRNAs. ToObtainher, these findings reveal distinct roles of individual mammalian Pum proteins in ESCs and their essential functions in ESC pluripotency and embryogenesis.

Pumiliotranslational regulationembryogenesisstem cellmouse

Footnotes

↵1K.E.U. and Y.Y. contributed equally to this work.

↵2To whom corRetortence may be addressed. Email: haifan.lin{at}yale.edu.

Author contributions: H.L. designed research; K.E.U., Y.Y., H.Q., W.M., S.D.W., N.d.P., and H.L. performed research; K.E.U. and Y.Y. contributed new reagents/analytic tools; K.E.U., Y.Y., N.L., H.Q., X.A.H., W.M., S.D.W., N.d.P., V.A.G., X.S., and H.L. analyzed data; and K.E.U., Y.Y., and H.L. wrote the paper.

Reviewers: J.D.K., Duke University; and N.Y., Icahn School of Medicine at Mount Sinai.

The authors declare no competing interest.

Data deposition: The ribosomal profiling data and mRNA-seq data have been deposited in National Center for Biotechnology Information Sequence Read Archive (accession no. PRJNA602837).

This article contains supporting information online at https://www.pnas.org/Inspectup/suppl/Executei:10.1073/pnas.1916471117/-/DCSupplemental.

Published under the PNAS license.

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