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

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.

Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment

“…RBPs are important regulators of mRNA stability through binding to the 3 0 untranslated regions of mRNAs (46). ZFP36L1 is an RBP that has been reported to regulate mouse embryonic stem cell fate through binding to mRNAs encoding pluripotency factors including Nanog (47). Here, we found that ZFP36L1 is phosphorylated and inactivated by the p38 substrate MK2, leading to stabilization of Nanog and Klf4 mRNA in TNBC cells.…”

X-chromosome dosage as a modulator of pluripotency, signalling and differentiation?

“…Through the activation of Mek and Erk, Fgf4 leads to the downregulation of Nanog at the transcriptional level, but also destabilizes Klf2 and Klf4 protein through Erk-dependent phosphorylation [22,23]. Moreover, Gsk3, which can mediate Wnt signalling has a differentiation promoting effect by repressing several pluripotency factors, [14], c [15], d [16], e [17], f [18], g [19], h [20], i [21], j [22], k [23], l [24], m [25], n [26], o [27].…”

“…Klf4 in turn induces the E3 ubiquitin ligase March5, which promotes the pluripotent state by inhibiting the Mek/Erk cascade [14]. Moreover, the AU-rich element mRNA binding protein Brf1 has been identified as an Erk target gene in mESCs and has been shown to bind and destabilize the mRNAs of several pluripotencyassociated genes, including Nanog [21]. This mechanism might mediate the long known Erk-dependent downregulation of Nanog [42].…”

Regulation of Pluripotency by RNA Binding Proteins

“…AUBPs are known to be developmentally important regulators of splicing, stability, translation, and localization, and Brf1 is critical in embryogenesis: knockout mice die by E10.5 (Stumpo et al, 2004). A recent study found that activation of the FGF-Erk signaling pathway, which stimulates mouse ESC differentiation, leads to upregulation of Brf1 (Tan and Elowitz, 2014). Brf1 overexpression under pluripotency conditions impaired ESC proliferation, and under differentiation conditions it promoted the acquisition of mesendoderm fate.…”