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Published April 29, 2014 | Supplemental Material + Published
Journal Article Open

Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase


AU-rich element mRNA-binding proteins (AUBPs) are key regulators of development, but how they are controlled and what functional roles they play depends on cellular context. Here, we show that Brf1 (zfp36l1), an AUBP from the Zfp36 protein family, operates downstream of FGF/Erk MAP kinase signaling to regulate pluripotency and cell fate decision making in mouse embryonic stem cells (mESCs). FGF/Erk MAP kinase signaling up-regulates Brf1, which disrupts the expression of core pluripotency-associated genes and attenuates mESC self-renewal without inducing differentiation. These regulatory effects are mediated by rapid and direct destabilization of Brf1 targets, such as Nanog mRNA. Enhancing Brf1 expression does not compromise mESC pluripotency but does preferentially regulate mesendoderm commitment during differentiation, accelerating the expression of primitive streak markers. Together, these studies demonstrate that FGF signals use targeted mRNA degradation by Brf1 to enable rapid posttranscriptional control of gene expression in mESCs.

Additional Information

© 2014 National Academy of Sciences. Edited by Gideon Dreyfuss, University of Pennsylvania, Philadelphia, PA, and approved March 25, 2014 (received for review November 6, 2013). Published ahead of print April 14, 2014. We thank Dr. Kathrin Plath (University of California, Los Angeles) and Dr. Angie Rizzino (University of Nebraska Medical Center) for the kind donation of cell culture reagents; Dr. Azim Surani (University of Cambridge) for fruitful discussions; Rochelle Diamond, Diana Perez, and Josh Verceles from the Caltech Flow Cytometry Facility; Igor Antoshechkin and Vijaya Kumar from the Millard and Muriel Jacobs Genetics and Genomics Laboratory at Caltech; Leah Santat, Yaron Antebi, Joe Markson, James Linton, Pierre Neveu, John Yong, Zakary Singer, Julia Tischler, Joe Levine, and Sandy Nandagopal for fruitful discussions. This work was supported by a Human Frontiers Science Program Grant (RGP0020/2012), the Weston Havens Foundation, and the David and Lucille Packard Foundation. F.E.T. was supported by the National Defense Science and Engineering Graduate Research Fellowship. Author contributions: F.E.T. and M.B.E. designed research; F.E.T. performed research; F.E.T. contributed new reagents/analytic tools; F.E.T. and M.B.E. analyzed data; and F.E.T. and M.B.E. wrote the paper. The authors declare no conflict of interest. This article is a PNAS Direct Submission. Data deposition: The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no. GSE40104). This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1320873111/-/DCSupplemental.

Attached Files

Published - PNAS-2014-Tan-E1740-8.pdf

Supplemental Material - pnas.201320873SI.pdf

Supplemental Material - sd01.xlsx

Supplemental Material - sd02.xlsx

Supplemental Material - sd03.xlsx

Supplemental Material - sd04.xlsx


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