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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 17; pp. E1740 - E1748
• Main Authors: Tan, Frederick E, Elowitz, Michael B
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.04.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; AU Rich Elements - genetics; Biological Sciences; Cell Differentiation - genetics; Cell Proliferation; Embryonic Stem Cells - cytology; Embryonic Stem Cells - enzymology; Endoderm - cytology; Extracellular Signal-Regulated MAP Kinases - metabolism; Fibroblast Growth Factors - metabolism; Gene expression; Gene Expression Regulation; Half-Life; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; MAP Kinase Signaling System; Mesoderm - cytology; Mice; Nanog Homeobox Protein; Nuclear Proteins - metabolism; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; PNAS Plus; Protein Binding - genetics; Proteins; Response Elements - genetics; Ribonucleic acid; RNA; RNA, Messenger - metabolism; RNA-Binding Proteins - metabolism; Rodents; Stem cells; Transcription, Genetic; Tristetraprolin - genetics; Tristetraprolin - metabolism; gene regulation dynamics; developmental signaling pathways; developmental mechanisms; stem cell biology; AU-rich element RNA-binding proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1320873111

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.