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

Tan, Frederick E. and Elowitz, Michael B. (2014) Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase. Proceedings of the National Academy of Sciences of the United States of America, 111 (17). E1740-E1748. ISSN 0027-8424. PMCID PMC4035916. https://resolver.caltech.edu/CaltechAUTHORS:20140421-105002893

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1320873111DOIArticle
http://www.pnas.org/content/111/17/E1740PublisherArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1320873111/-/DCSupplementalPublisherSupporting Information
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035916/PubMed CentralArticle
ORCID:
AuthorORCID
Elowitz, Michael B.0000-0002-1221-0967
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.
Funders:
Funding AgencyGrant Number
Human Frontier Science ProgramRGP0020/2012
Weston Havens FoundationUNSPECIFIED
David and Lucile Packard FoundationUNSPECIFIED
National Defense Science and Engineering Graduate (NDSEG) FellowshipUNSPECIFIED
Subject Keywords:stem cell biology; AU-rich element RNA-binding proteins; developmental mechanisms; developmental signaling pathways; gene regulation dynamics
Issue or Number:17
PubMed Central ID:PMC4035916
Record Number:CaltechAUTHORS:20140421-105002893
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140421-105002893
Official Citation:Tan, F. E., & Elowitz, M. B. (2014). Brf1 posttranscriptionally regulates pluripotency and differentiation responses downstream of Erk MAP kinase. Proceedings of the National Academy of Sciences. doi: 10.1073/pnas.1320873111
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:45072
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:21 Apr 2014 21:24
Last Modified:03 Oct 2019 06:26

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