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MicroRNAs: key regulators of stem cells

Key Points

  • Embryonic and adult tissue stem cells are characterized by their ability to self-renew and to differentiate into daughter cells, which in adult tissue stem cells is often achieved by asymmetric divisions.

  • MicroRNAs (miRNAs) are 20–25-nucleotide (nt)-long non-coding RNAs that bind to the 3′ untranslated region of target mRNAs via imperfect match to repress their translation and stability.

  • miRNAs fine-tune self-renewal and differentiation pathways of stem cells by regulating the intracellular levels of the key protein factors that are involved in these processes. It is now clear that a number of miRNAs that are involved in stem cell processes are co-expressed as clusters and can function as 'master regulators' of stem cell processes.

  • miRNAs and the transcriptional machinery form an integral network that regulates stem cell processes.

  • In addition to miRNA, there are two other types of small RNAs: endogenous small interfering RNAs (endo-siRNAs) and Piwi-interacting RNAs (piRNAs). Their presence and function in stem cells is not known.

  • The recent advent of next generation sequencing technologies has increased our ability to identify new miRNAs and other small RNAs in various tissues.

Abstract

The hallmark of a stem cell is its ability to self-renew and to produce numerous differentiated cells. This unique property is controlled by dynamic interplays between extrinsic signalling, epigenetic, transcriptional and post-transcriptional regulations. Recent research indicates that microRNAs (miRNAs) have an important role in regulating stem cell self-renewal and differentiation by repressing the translation of selected mRNAs in stem cells and differentiating daughter cells. Such a role has been shown in embryonic stem cells, germline stem cells and various somatic tissue stem cells. These findings reveal a new dimension of gene regulation in controlling stem cell fate and behaviour.

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Figure 1: RNA regulation of embryonic stem cells.
Figure 2: RNA regulation of haematopoietic stem cells.

References

  1. 1

    Sell, S. Stem Cells Handbook (Humana, Totowa, New Jersey, 2003).

    Book  Google Scholar 

  2. 2

    Lin, H. Cell biology of stem cells: an enigma of asymmetry and self-renewal. J. Cell Biol. 180, 257–260 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Lin, H. The stem-cell niche theory: lessons from flies. Nature Rev. Genet. 3, 931–940 (2002).

    CAS  Article  Google Scholar 

  4. 4

    Blakaj, A. & Lin, H. Piecing together the mosaic of early mammalian development through microRNAs. J. Biol. Chem. 283, 9505–9508 (2008).

    CAS  Article  Google Scholar 

  5. 5

    Rana, T. M. Illuminating the silence: understanding the structure and function of small RNAs. Nature Rev. Mol. Cell Biol. 8, 23–36 (2007).

    CAS  Article  Google Scholar 

  6. 6

    Vasudevan, S., Tong, Y. & Steitz, J. A. Switching from repression to activation: microRNAs can up-regulate translation. Science 318, 1931–1934 (2007). Provides the first evidence for translational activation by miRNAs.

    CAS  Article  Google Scholar 

  7. 7

    Okamura, K., Hagen, J. W., Duan, H., Tyler, D. M. & Lai, E. C. The mirtron pathway generates microRNA-class regulatory RNAs in Drosophila. Cell 130, 89–100 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Ruby, J. G., Jan, C. H. & Bartel, D. P. Intronic microRNA precursors that bypass Drosha processing. Nature 448, 83–86 (2007).

    CAS  Article  Google Scholar 

  9. 9

    Babiarz, J. E., Ruby, J. G., Wang, Y., Bartel, D. P. & Blelloch, R. Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev. 22, 2773–2785 (2008). References 7–9 introduce new pathways for miRNA biogenesis. Reference 9 also shows that endogenous siRNAs are expressed in mouse ES cells.

    CAS  Article  Google Scholar 

  10. 10

    Okamura, K. & Lai, E. C. Endogenous small interfering RNAs in animals. Nature Rev. Mol. Cell Biol. 9, 673–678 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Lin, H. piRNAs in the germ line. Science 316, 397 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Yin, H. & Lin, H. An epigenetic activation role of Piwi and a Piwi-associated piRNA in Drosophila melanogaster. Nature 450, 304–308 (2007). Provides the first evidence that piRNAs mediate epigenetic activation.

    CAS  Article  Google Scholar 

  13. 13

    Houbaviy, H. B., Murray, M. F. & Sharp, P. A. Embryonic stem cell-specific microRNAs. Dev. Cell 5, 351–358 (2003). Provides the earliest evidence for the existence of ES cell-specific miRNAs and also evidence that self-renewing and differentiating ES cells have distinct miRNAs.

    CAS  Article  Google Scholar 

  14. 14

    Tomari, Y. & Zamore, P. D. Perspective: machines for RNAi. Genes Dev. 19, 517–529 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Bernstein, E. et al. Dicer is essential for mouse development. Nature Genet. 35, 215–217 (2003).

    CAS  Article  Google Scholar 

  16. 16

    Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005). References 15 and 16 describe the biological function of Dicer in mouse embryonic stem cells.

    CAS  Article  Google Scholar 

  17. 17

    Calabrese, J. M., Seila, A. C., Yeo, G. W. & Sharp, P. A. RNA sequence analysis defines Dicer's role in mouse embryonic stem cells. Proc. Natl Acad. Sci. USA 104, 18097–18102 (2007).

    CAS  Article  Google Scholar 

  18. 18

    Wang, Y., Medvid, R., Melton, C., Jaenisch, R. & Blelloch, R. DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nature Genet. 39, 380–385 (2007). Shows the specific requirement of the miRNA pathway for stem cell differentiation and cell cycle control.

    CAS  Article  Google Scholar 

  19. 19

    Suh, M. R. et al. Human embryonic stem cells express a unique set of microRNAs. Dev. Biol. 270, 488–498 (2004). This reference, along with reference 10, provides evidence for distinct miRNA signatures for self-renewing and differentiating stem cells.

    CAS  Article  Google Scholar 

  20. 20

    Morin, R. D. et al. Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res. 18, 610–621 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Neilson, J. R., Zheng, G. X., Burge, C. B. & Sharp, P. A. Dynamic regulation of miRNA expression in ordered stages of cellular development. Genes Dev. 21, 578–589 (2007).

    CAS  Article  Google Scholar 

  22. 22

    Nakano, M. et al. Plant MPSS databases: signature-based transcriptional resources for analyses of mRNA and small RNA. Nucleic Acids Res. 34, D731–D735 (2006).

    CAS  Article  Google Scholar 

  23. 23

    Margulies, M. et al. Genome sequencing in microfabricated high-density picolitre reactors. Nature 437, 376–380 (2005).

    CAS  Article  Google Scholar 

  24. 24

    Hafner, M. et al. Identification of microRNAs and other small regulatory RNAs using cDNA library sequencing. Methods 44, 3–12 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Hayashi, K. et al. MicroRNA biogenesis is required for mouse primordial germ cell development and spermatogenesis. PLoS ONE 3, e1738 (2008).

    Article  Google Scholar 

  26. 26

    Singh, S. K., Kagalwala, M. N., Parker-Thornburg, J., Adams, H. & Majumder, S. REST maintains self-renewal and pluripotency of embryonic stem cells. Nature 453, 223–227 (2008).

    CAS  Article  Google Scholar 

  27. 27

    Tay, Y., Zhang, J., Thomson, A. M., Lim, B. & Rigoutsos, I. MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 455, 1124–1128 (2008). Shows, for the first time, that miRNAs can also target coding regions instead of the 3′ UTR, and regulate translation of cognate mRNAs.

    CAS  Article  Google Scholar 

  28. 28

    Marson, A. et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell 134, 521–533 (2008). Shows, on a global scale, that key ES cell-specific transcription factors directly associate with promoter regions of ES cell-specific miRNAs, and thereby provides a mechanistic link between transcription factors and miRNA-dependent ES cell regulation.

    CAS  Article  Google Scholar 

  29. 29

    Benetti, R. et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nature Struct. Biol. 15, 268–279 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Sinkkonen, L. et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nature Struct. Biol. 15, 259–267 (2008).

    CAS  Article  Google Scholar 

  31. 31

    Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).

    CAS  Article  Google Scholar 

  32. 32

    Viswanathan, S. R., Daley, G. Q. & Gregory, R. I. Selective blockade of microRNA processing by Lin28. Science 320, 97–100 (2008).

    CAS  Article  Google Scholar 

  33. 33

    Rybak, A. et al. A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment. Nature Cell Biol. 10, 987–993 (2008).

    CAS  Article  Google Scholar 

  34. 34

    Newman, M. A., Thomson, J. M. & Hammond, S. M. Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. RNA 14, 1539–1549 (2008).

    CAS  Article  Google Scholar 

  35. 35

    Georgantas, R. W. 3rd et al. CD34+ hematopoietic stem-progenitor cell microRNA expression and function: a circuit diagram of differentiation control. Proc. Natl Acad. Sci. USA 104, 2750–2755 (2007).

    CAS  Article  Google Scholar 

  36. 36

    Chen, C. Z., Li, L., Lodish, H. F. & Bartel, D. P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004). Provides the first evidence that miRNAs are involved in the differentiation of an adult stem cell lineage.

    CAS  Article  Google Scholar 

  37. 37

    Bruchova, H., Yoon, D., Agarwal, A. M., Mendell, J. & Prchal, J. T. Regulated expression of microRNAs in normal and polycythemia vera erythropoiesis. Exp. Hematol. 35, 1657–1667 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Wang, Q. et al. MicroRNA miR-24 inhibits erythropoiesis by targeting activin type I receptor ALK4. Blood 111, 588–595 (2008).

    CAS  Article  Google Scholar 

  39. 39

    Felli, N. et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc. Natl Acad. Sci. USA 102, 18081–18086 (2005).

    CAS  Article  Google Scholar 

  40. 40

    Fontana, L. et al. MicroRNAs 17-5p–20a–106a control monocytopoiesis through AML1 targeting and M-CSF receptor upregulation. Nature Cell Biol. 9, 775–787 (2007).

    CAS  Article  Google Scholar 

  41. 41

    Zhou, B., Wang, S., Mayr, C., Bartel, D. P. & Lodish, H. F. miR-150, a microRNA expressed in mature B and T cells, blocks early B cell development when expressed prematurely. Proc. Natl Acad. Sci. USA 104, 7080–7085 (2007).

    CAS  Article  Google Scholar 

  42. 42

    Dore, L. C. et al. A GATA-1-regulated microRNA locus essential for erythropoiesis. Proc. Natl Acad. Sci. USA 105, 3333–3338 (2008).

    CAS  Article  Google Scholar 

  43. 43

    Rosa, A. et al. The interplay between the master transcription factor PU.1 and miR-424 regulates human monocyte/macrophage differentiation. Proc. Natl Acad. Sci. USA 104, 19849–19854 (2007).

    CAS  Article  Google Scholar 

  44. 44

    Buckingham, M. Myogenic progenitor cells and skeletal myogenesis in vertebrates. Curr. Opin. Genet. Dev. 16, 525–532 (2006).

    CAS  Article  Google Scholar 

  45. 45

    Chen, J. F. et al. The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nature Genet. 38, 228–233 (2006).

    CAS  Article  Google Scholar 

  46. 46

    Anderson, C., Catoe, H. & Werner, R. MIR-206 regulates connexin43 expression during skeletal muscle development. Nucleic Acids Res. 34, 5863–5871 (2006).

    CAS  Article  Google Scholar 

  47. 47

    McCarthy, J. J. MicroRNA-206: the skeletal muscle-specific myomiR. Biochim. Biophys. Acta 1779, 682–691 (2008).

    CAS  Article  Google Scholar 

  48. 48

    Ivey, K. N. et al. MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2, 219–229 (2008).

    CAS  Article  Google Scholar 

  49. 49

    Wong, C. F. & Tellam, R. L. MicroRNA-26a targets the histone methyltransferase enhancer of zeste homolog 2 during myogenesis. J. Biol. Chem. 283, 9836–9843 (2008).

    CAS  Article  Google Scholar 

  50. 50

    Caretti, G., Di Padova, M., Micales, B., Lyons, G. E. & Sartorelli, V. The polycomb Ezh2 methyltransferase regulates muscle gene expression and skeletal muscle differentiation. Genes Dev. 18, 2627–2638 (2004).

    CAS  Article  Google Scholar 

  51. 51

    Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).

    CAS  Article  Google Scholar 

  52. 52

    Rao, P. K., Kumar, R. M., Farkhondeh, M., Baskerville, S. & Lodish, H. F. Myogenic factors that regulate expression of muscle-specific microRNAs. Proc. Natl Acad. Sci. USA 103, 8721–8726 (2006).

    CAS  Article  Google Scholar 

  53. 53

    Sun, Q. et al. Transforming growth factor-β-regulated miR-24 promotes skeletal muscle differentiation. Nucleic Acids Res. 36, 2690–2699 (2008).

    CAS  Article  Google Scholar 

  54. 54

    Shi, Y., Sun, G., Zhao, C. & Stewart, R. Neural stem cell self-renewal. Crit. Rev. Oncol. Hematol. 65, 43–53 (2008).

    Article  Google Scholar 

  55. 55

    Smirnova, L. et al. Regulation of miRNA expression during neural cell specification. Eur. J. Neurosci. 21, 1469–1477 (2005).

    Article  Google Scholar 

  56. 56

    Krichevsky, A. M., Sonntag, K. C., Isacson, O. & Kosik, K. S. Specific microRNAs modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857–864 (2006).

    CAS  Article  Google Scholar 

  57. 57

    Visvanathan, J., Lee, S., Lee, B., Lee, J. W. & Lee, S. K. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007).

    CAS  Article  Google Scholar 

  58. 58

    Yeo, M. et al. Small CTD phosphatases function in silencing neuronal gene expression. Science 307, 596–600 (2005).

    CAS  Article  Google Scholar 

  59. 59

    Heino, T. J. & Hentunen, T. A. Differentiation of osteoblasts and osteocytes from mesenchymal stem cells. Curr. Stem Cell Res. Ther. 3, 131–145 (2008).

    CAS  Article  Google Scholar 

  60. 60

    Mizuno, Y. et al. miR-125b inhibits osteoblastic differentiation by down-regulation of cell proliferation. Biochem. Biophys. Res. Commun. 368, 267–272 (2008).

    CAS  Article  Google Scholar 

  61. 61

    Luzi, E. et al. Osteogenic differentiation of human adipose tissue-derived stem cells is modulated by the miR-26a targeting of the SMAD1 transcription factor. J. Bone Miner. Res. 23, 287–295 (2008).

    CAS  Article  Google Scholar 

  62. 62

    Andl, T. et al. The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles. Curr. Biol. 16, 1041–1049 (2006).

    CAS  Article  Google Scholar 

  63. 63

    Yi, R. et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nature Genet. 38, 356–362 (2006).

    CAS  Article  Google Scholar 

  64. 64

    Yi, R., Poy, M. N., Stoffel, M. & Fuchs, E. A skin microRNA promotes differentiation by repressing 'stemness'. Nature 452, 225–229 (2008).

    CAS  Article  Google Scholar 

  65. 65

    Megosh, H. B., Cox, D. N., Campbell, C. & Lin, H. The role of PIWI and the miRNA machinery in Drosophila germline determination. Curr. Biol. 16, 1884–1894 (2006).

    CAS  Article  Google Scholar 

  66. 66

    Park, J. K., Liu, X., Strauss, T. J., McKearin, D. M. & Liu, Q. The miRNA pathway intrinsically controls self-renewal of Drosophila germline stem cells. Curr. Biol. 17, 533–538 (2007).

    CAS  Article  Google Scholar 

  67. 67

    Forstemann, K. et al. Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein. PLoS Biol. 3, e236 (2005).

    Article  Google Scholar 

  68. 68

    Hatfield, S. D. et al. Stem cell division is regulated by the microRNA pathway. Nature 435, 974–978 (2005).

    CAS  Article  Google Scholar 

  69. 69

    Knight, S. W. & Bass, B. L. A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science 293, 2269–2271 (2001).

    CAS  Article  Google Scholar 

  70. 70

    Beyret, E. & Lin, H. in MicroRNAs — from Basic Science to Disease Biology (ed. Appasani, K.) 497–511 (Cambridge Univ. Press, New York, 2008).

    Google Scholar 

  71. 71

    Palakodeti, D., Smielewska, M., Lu, Y. C., Yeo, G. W. & Graveley, B. R. The PIWI proteins SMEDWI-2 and SMEDWI-3 are required for stem cell function and piRNA expression in planarians. RNA 14, 1174–1186 (2008).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank members of the Lin laboratory for their valuable comments on the manuscript. We apologize to those whose works are not cited here owing to space limitations. The stem cell work done in the Lin laboratory is supported by National Institutes of Health Grants HD33760, HD37760S1 and HD42042, the Connecticut Stem Cell Research Fund, the G. Harold and Leila Mathers Foundation and the Stem Cell Research Foundation.

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Correspondence to Haifan Lin.

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DATABASES

The miRNA registry

let-7

miR-1

miR-15b

miR-16

miR-17

miR-20a

miR-21

miR-22

miR-23

miR-24

miR-26a

miR-29

miR-106a

miR-124

miR-125b

miR-128

miR-133

miR-134

miR-144

miR-150

miR-155

miR-181

miR-203

miR-206

miR-221

miR-222

miR-223

miR-290

miR-296

miR-301

miR-302

miR-424

miR-451

miR-470

FURTHER INFORMATION

Haifan Lin's homepage

Glossary

Blastocyst

An early stage of embryonic development at which cells begin to commit to two developmental lineages: the inner cell mass, which gives rise to the fetus, and the trophoblast, which gives rise to fetal support tissues, such as the placenta and the umbilical cord.

Niche

The natural anatomical microenvironment that supports stem cell behaviour.

Spliceosome

A ribonucleoprotein (RNP) complex that is involved in splicing of nuclear pre-mRNA. It is composed of five small nuclear (sn) RNPs and more than 50 non-snRNPs, which recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.

Piwi

An Argonaute or Piwi protein family member in Drosophila melanogaster that is required for germline stem cell self-renewal and also binds to 25 nucleotide small RNAs. Piwi is the founding member that was used to define the protein family.

Transposon

A mobile genetic element that can relocate within the genome of its host. An autonomous transposon encodes a transposase protein that catalyses its excision and reintegration in the genome, and can therefore direct its own transposition.

Gap junction

An intercellular connection that directly connects cytoplasm of two cells so that exchange of molecules and ions can occur freely.

Neoblast

An undifferentiated cell in annelids that proliferates to produce differentiated cells at the sites of repair.

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Gangaraju, V., Lin, H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol 10, 116–125 (2009). https://doi.org/10.1038/nrm2621

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