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LIN28/LET-7-Axis

Discovered the LIN28/let-7 axis.

We discovered LIN28 as the first negative regulator of the miRNA biogenesis pathway. Members of the let-7 family are coordinately regulated during development with let-7 expressed at high levels in differentiated cell types. During differentiation of embryonic stem cells (ESCs), mature let-7 miRNAs accumulate but the corresponding primary let-7 transcript remains constant implying posttranscriptional control of miRNA expression, the mechanism for which had remained elusive. We identified the RNA-binding protein LIN28 as a stem cell-specific regulator of miRNA biogenesis. LIN28 was originally discovered as a developmental timing regulator in C. elegans, and later as a reprogramming factor for induced pluripotent stem cells (iPSCs). Since LIN28 mRNA is itself a let-7 target, this LIN28/let-7 axis establishes a double-negative feedback loop, whereby high expression levels of either let-7 or LIN28 will promote a differentiated or embryonic cell fate, respectively. Since the publication of our influential first paper, my laboratory has focused on providing mechanistic insight into this pathway. In carrying out these studies, we established a new area of research that profoundly impacts the study of stem cell biology along with many other areas including cancer. This fundamental discovery launched a new area of research for several other labs, and there is a growing appreciation that the LIN28/let-7 pathway is involved in a sweeping range of biology: germ cell development, somatic cell reprogramming, cancer, aging, inflammation, hematopoiesis, glycolytic metabolism, and diabetes.

  1. Viswanathan S. R., Daley G. Q., and Gregory R. I. Selective blockade of microRNA processing by Lin28. Science 2008, 320, 97-100. PMID: 18292307. PMC3368499.
  2. Piskounova E., Polytarchou C., Thornton J. E., Hagan J.P., LaPierre R. J., Pothoulakis C., Iliopoulos D., and Gregory R. I. Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell 2011, 147, 1066-79. PMID: 22118463. PMC3227872.