Page Menu

MicroRNA Stem Cell Biology

Identified pathways controlling miRNA biogenesis/function and stem cell pluripotency.

We identified Trim71 as stem cell specific Ago2-associated protein and found that Trim71 cooperates with miRNAs to repress expression of Cdkn1a, a cyclin-dependent kinase inhibitor that negatively regulates the G1–S transition. Thus, Trim71 represents a novel ‘stemness’ gene that promotes rapid ESC self-renewal. Our characterization of Ago2 complexes in ESCs led to our discovery that Ago2 protein is unstable and rapidly degraded by the lysosome unless bound by small RNAs and found that the co-chaperones Fkbp4/5 are required for the loading of Ago2 with siRNA and miRNAs. By exploring the mechanism responsible for the dynamic posttranscriptional control of miR-17~92 during ESC differentiation, we identified a novel miRNA biogenesis intermediate termed progenitor miRNA (pro-miRNA). Pri-miR-17~92 adopts an RNA conformation that selectively blocks Microprocessor. Thus, developmentally regulated pro-miRNA processing is key step controlling miRNA expression and explains the posttranscriptional control of miR-17~92 expression in development, thereby revealing a new paradigm for miRNA control. Following up on this dynamic regulation we identified an intermediate ‘poised’ pluripotent state characterized by specific mRNA and miRNA transcriptomes and ability to contribute to mouse chimeras. ISY1-mediated miRNA regulation is necessary and sufficient for establishing poised pluripotency required for naïve-primed transition, providing an explanation for the early embryonic-lethality of global miRNA deficiency.

  1. Chang H., Martinez N. J., Thornton J. E., Hagan J. P., Nguyen K. D., and Gregory R. I. Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nature Commun 2012, 3, 923. PMID: 22735451. PMC3518406.
  2. Martinez N. J., Chang H-M., Borrajo J., and Gregory R. I. The co-chaperones Fkbp4/5 control Argonaute2 expression and facilitate RISC assembly. RNA 2013, 11, 1583-93. PMID: 24049110. PMC3851725.
  3. Du, P., Wang, L., Sliz, P., and Gregory, R. I. A biogenesis step upstream of microprocessor controls miR-17~92 expression. Cell 2015, 162, 885-899. PMID: 26255770. PMC4537828.
  4. Du P., Pirouz M., Choi J., Huebner A. J., Clement K., Meissner A., Hochedlinger K., and Gregory R. I. An intermediate pluripotent state controlled by microRNAs Is required for the naive-to-primed stem cell transition. Cell Stem Cell 2018, 22, 851-64. PMID: 29804889. PMC5990487.

  5. Cui Y., Lyu X., Ding L., Ke L., Yang D., Pirouz M., Qi Y., Ong J., Gao G., Du P., and Gregory R. I. Global miRNA dosage control of embryonic germ layer specification. Nature 2021, 593, 602-606. PMID: 33953397. PMC8297444.