Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions
- 1Department of Pathology, University of California, San Francisco, San Francisco, California, United States of America
- 2The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Center for Reproductive Sciences, University of California, San Francisco, San Francisco, California, United States of America
- 3Department of Urology, University of California, San Francisco, San Francisco, California, United States of America
Abstract
Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3’untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation. Author summary: Embryonic stem cells can give rise to every cell type in the body, but this requires precise regulation of gene expression as development progresses. Although much is known about how genes are turned on and off, less is understood about how cells fine-tune the messenger RNA (mRNA) transcripts to mold the final messages that make proteins. Here, we show that two distinct mRNA regulatory mechanisms cooperate to control expression of Profilin-2 (Pfn2), a gene expressed in early embryonic development. We found that neighboring binding sites for embryonic stem cell-enriched microRNAs and Iron Regulatory Proteins (IRPs) within the Pfn2 mRNA have different functions during development. Loss of the microRNA binding site increases PFN2 levels and disrupts the transition from pluripotency by reducing FGF signaling. In contrast, loss of the IRP binding site decreases PFN2 levels, impairs Wnt/β-catenin signaling, and blocks formation of the mesendoderm embryonic cell lineages. Together, our findings identify Pfn2 as a critical post-transcriptional regulatory node that coordinates successive developmental transitions and reveal how precise regulation of a single mRNA can determine cell fate during early embryonic development.
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BibTeX
@article{sangokoya2026posttranscriptional,
title = {{Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions}},
author = {Carolyn Sangokoya and Isabella R. Rosso and Rana Ghandehari-Alavijeh and Robert Blelloch},
journal = {PLOS Genetics},
year = {2026},
month = sep,
doi = {10.1371/journal.pgen.1012279},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012279},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions
AU - Carolyn Sangokoya
AU - Isabella R. Rosso
AU - Rana Ghandehari-Alavijeh
AU - Robert Blelloch
PY - 2026
DA - 2026/09/02
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012279
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012279
AB - Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3’untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation. Author summary: Embryonic stem cells can give rise to every cell type in the body, but this requires precise regulation of gene expression as development progresses. Although much is known about how genes are turned on and off, less is understood about how cells fine-tune the messenger RNA (mRNA) transcripts to mold the final messages that make proteins. Here, we show that two distinct mRNA regulatory mechanisms cooperate to control expression of Profilin-2 (Pfn2), a gene expressed in early embryonic development. We found that neighboring binding sites for embryonic stem cell-enriched microRNAs and Iron Regulatory Proteins (IRPs) within the Pfn2 mRNA have different functions during development. Loss of the microRNA binding site increases PFN2 levels and disrupts the transition from pluripotency by reducing FGF signaling. In contrast, loss of the IRP binding site decreases PFN2 levels, impairs Wnt/β-catenin signaling, and blocks formation of the mesendoderm embryonic cell lineages. Together, our findings identify Pfn2 as a critical post-transcriptional regulatory node that coordinates successive developmental transitions and reveal how precise regulation of a single mRNA can determine cell fate during early embryonic development.
SN - 1553-7404
ER -