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Regulation of microRNA function in somatic stem cell proliferation and differentiation

Nature Reviews Molecular Cell Biology volume 15, pages 565–576 (2014)Cite this article

Subjects

Key Points

  • MicroRNAs (miRNAs) constitute an essential part of the gene networks that drive proliferation, viability and differentiation of stem and progenitor cells across different somatic lineages.

  • Upstream of miRNAs is a network of cell type-specific transcription factors that function together with epigenetic regulators to tightly regulate miRNA levels spatially and temporally. miRNA levels are further fine-tuned through post-transcriptional mechanisms regulating their processing to the mature form as well as their stability.

  • Downstream of miRNAs are large networks of mRNA targets that influence cell fate choice. Through suppression of these targets, the miRNAs can silence previously active or alternative gene programmes during cell fate transitions.

  • The impact of any one miRNA on a particular mRNA target is influenced by multiple factors, including the number of available target sites within the mRNA, targeting of the mRNA simultaneously by other miRNAs and competition between targets for the same miRNA.

  • Availability of and affinity to miRNA target sites within mRNAs is influenced by factors such as alternative splicing, alternative polyadenylation and RNA-binding protein synergism or antagonism to miRNA binding.

Abstract

microRNAs (miRNAs) are important modulators of development. Owing to their ability to simultaneously silence hundreds of target genes, they have key roles in large-scale transcriptomic changes that occur during cell fate transitions. In somatic stem and progenitor cells — such as those involved in myogenesis, haematopoiesis, skin and neural development — miRNA function is carefully regulated to promote and stabilize cell fate choice. miRNAs are integrated within networks that form both positive and negative feedback loops. Their function is regulated at multiple levels, including transcription, biogenesis, stability, availability and/or number of target sites, as well as their cooperation with other miRNAs and RNA-binding proteins. Together, these regulatory mechanisms result in a refined molecular response that enables proper cellular differentiation and function.

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Figure 1: Regulation of miRNA biogenesis and function occurs at multiple levels.
Figure 2: Lineage-restricted stem and progenitor cell differentiation during the development of four model lineages.
Figure 3: miRNA regulation during myogenesis.
Figure 4: miRNAs regulate cell fate choices and differentiation during haematopoiesis.
Figure 5: miRNAs regulate the development of the epidermis and hair follicle.
Figure 6: miRNAs regulate the development of neural cells.

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Acknowledgements

The authors would like to thank members of the Blelloch laboratory, especially A. Chen, J. Freimer, R. Krishnakumar and M. Shveygert for helpful discussions and comments. This work was funded by a CIRM training grant TG2-01153 (A.S.) and grants to R.H.B. from the US National Institutes of Health (R01 NS057221 and GM101180) and the California Institute of Regenerative Medicine (New Faculty Award, RN2-00906-1).

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  1. Center for Reproductive Sciences and Department of Urology, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94143–0667, California, USA

    Archana Shenoy & Robert H. Blelloch

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Correspondence to Robert H. Blelloch.

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A family of proteins that function as effectors of microRNA (miRNA) function. Along with other proteins, such as GW182, they form a complex with miRNAs and bind target mRNAs to promote translational inhibition or mRNA degradation.

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Shenoy, A., Blelloch, R. Regulation of microRNA function in somatic stem cell proliferation and differentiation. Nat Rev Mol Cell Biol 15, 565–576 (2014). https://doi.org/10.1038/nrm3854

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