Current Stem Cell Reports

, Volume 4, Issue 2, pp 158–165 | Cite as

Molecular Moirai: Long Noncoding RNA Mediators of HSC Fate

  • Nathaniel Magilnick
  • Mark P. Boldin
Role of Classical Signaling Pathways in Stem Cell Maintenance (A Cardoso and N Carlesso, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Role of Classical Signaling Pathways in Stem Cell Maintenance


Purpose of Review

Hematopoiesis is an ordered developmental process that requires dynamic regulation to warrant proper response to physiological challenges and prevent malignancies. Long noncoding RNAs are emerging as key, multi-faceted regulators of gene expression. This review explores the function of lncRNAs in the control of hematopoietic stem cell (HSC) homeostasis and hematopoietic differentiation.

Recent Findings

Multiple lncRNAs have been implicated in maintaining HSC stemness and enabling progenitors to carry out the correct programs of lineage differentiation. Specific lncRNAs have been identified that regulate the differentiation of multipotent progenitors into terminally differentiated blood cells. These lncRNAs predominantly act by assisting master regulators that drive specific differentiation programs, either by enhancing or repressing the transcription of particular genomic loci.


Long noncoding RNAs contribute to the correct differentiation and maturation of various hematopoietic lineages by assisting with the activation of transcriptional programs in a time- and cell-dependent manner.


Hematopoiesis Long noncoding RNA HSC Cell fate Differentiation 


Funding information

This work was supported by the National Cancer Institute of the NIH under Award P30CA033572. This work was funded in part by the NIH AI125615, the Nesvig Lymphoma Research Fund at the City of Hope and the Research Career Development award (to M.P.B.) by the STOP CANCER Foundation.

Compliance with Ethical Standards

Conflict of Interest

Nathaniel Magilnick and Mark P. Boldin declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Morrison JV. Kerostasia, the dictates of fate, and the will of Zeus in the Iliad. Arethusa. 1997;30:276–96.CrossRefGoogle Scholar
  2. 2.
    Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132(4):631–44. Scholar
  3. 3.
    Cabezas-Wallscheid N, Eichwald V, de Graaf J, Lower M, Lehr HA, Kreft A, et al. Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mouse model. EMBO Mol Med. 2013;5(12):1804–20. Scholar
  4. 4.
    Deveson IW, Hardwick SA, Mercer TR, Mattick JS. The dimensions, dynamics, and relevance of the mammalian noncoding transcriptome. Trends Genet. 2017;33(7):464–78. Scholar
  5. 5.
    Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66. Scholar
  6. 6.
    Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136(2):215–33. Scholar
  7. 7.
    Mehta A, Baltimore D. MicroRNAs as regulatory elements in immune system logic. Nat Rev Immunol. 2016;16(5):279–94. Scholar
  8. 8.
    Montagner S, Deho L, Monticelli S. MicroRNAs in hematopoietic development. BMC Immunol. 2014;15:14. Scholar
  9. 9.
    Baltimore D, Boldin MP, O’Connell RM, Rao DS, Taganov KD. MicroRNAs: new regulators of immune cell development and function. Nat Immunol. 2008;9(8):839–45. Scholar
  10. 10.
    •• Luo M, Jeong M, Sun D, Park HJ, Rodriguez BA, Xia Z, et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell. 2015;16(4):426–38. Identification and characterization of lnc-HSC1/2 in hematopoietic stem cells. The first HSC-specific lncRNAs whose functions have been experimentally verified. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Venkatraman A, He XC, Thorvaldsen JL, Sugimura R, Perry JM, Tao F, et al. Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence. Nature. 2013;500(7462):345–9. Scholar
  12. 12.
    Yildirim E, Kirby JE, Brown DE, Mercier FE, Sadreyev RI, Scadden DT, et al. Xist RNA is a potent suppressor of hematologic cancer in mice. Cell. 2013;152(4):727–42. Scholar
  13. 13.
    Chaligne R, Heard E. X-chromosome inactivation in development and cancer. FEBS Lett. 2014;588(15):2514–22. Scholar
  14. 14.
    Li G, Su Q, Liu GQ, Gong L, Zhang W, Zhu SJ, et al. Skewed X chromosome inactivation of blood cells is associated with early development of lung cancer in females. Oncol Rep. 2006;16(4):859–64.PubMedGoogle Scholar
  15. 15.
    Zhang X, Lian Z, Padden C, Gerstein MB, Rozowsky J, Snyder M, et al. A myelopoiesis-associated regulatory intergenic noncoding RNA transcript within the human HOXA cluster. Blood. 2009;113(11):2526–34. Scholar
  16. 16.
    Alvarez-Dominguez JR, Hu W, Yuan B, Shi J, Park SS, Gromatzky AA, et al. Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation. Blood. 2014;123(4):570–81. Scholar
  17. 17.
    •• Kotzin JJ, Spencer SP, McCright SJ, Kumar DBU, Collet MA, Mowel WK, et al. The long non-coding RNA Morrbid regulates Bim and short-lived myeloid cell lifespan. Nature. 2016;537(7619):239–43. Discovery and functional verification of the myeloid cell lncRNA Morrbid which acts to repress a target locus in an allele specific manner. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wagner LA, Christensen CJ, Dunn DM, Spangrude GJ, Georgelas A, Kelley L, et al. EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression. Blood. 2007;109(12):5191–8. Scholar
  19. 19.
    Chen MT, Lin HS, Shen C, Ma YN, Wang F, Zhao HL, et al. PU.1-regulated long noncoding RNA lnc-MC controls human monocyte/macrophage differentiation through interaction with microRNA 199a-5p. Mol Cell Biol. 2015;35(18):3212–24. PubMedPubMedCentralGoogle Scholar
  20. 20.
    • Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, et al. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344(6181):310–3. Identification of the lncRNA lnc-DC which is important for dendritic cell differentiation. CrossRefPubMedGoogle Scholar
  21. 21.
    Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, et al. A strategy for probing the function of noncoding RNAs finds a repressor of NFAT. Science. 2005;309(5740):1570–3. Scholar
  22. 22.
    Gomez JA, Wapinski OL, Yang YW, Bureau JF, Gopinath S, Monack DM, et al. The NeST long ncRNA controls microbial susceptibility and epigenetic activation of the interferon-gamma locus. Cell. 2013;152(4):743–54. Scholar
  23. 23.
    Huang W, Thomas B, Flynn RA, Gavzy SJ, Wu L, Kim SV, et al. DDX5 and its associated lncRNA Rmrp modulate TH17 cell effector functions. Nature. 2015;528(7583):517–22. Scholar
  24. 24.
    Hu G, Tang Q, Sharma S, Yu F, Escobar TM, Muljo SA, et al. Expression and regulation of intergenic long noncoding RNAs during T cell development and differentiation. Nat Immunol. 2013;14(11):1190–8. Scholar
  25. 25.
    Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157(1):77–94. Scholar
  26. 26.
    Iyer MK, Niknafs YS, Malik R, Singhal U, Sahu A, Hosono Y, et al. The landscape of long noncoding RNAs in the human transcriptome. Nat Genet. 2015;47(3):199–208. Scholar
  27. 27.
    Cabezas-Wallscheid N, Klimmeck D, Hansson J, Lipka DB, Reyes A, Wang Q, et al. Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis. Cell Stem Cell. 2014;15(4):507–22. Scholar
  28. 28.
    Chambers SM, Boles NC, Lin KY, Tierney MP, Bowman TV, Bradfute SB, et al. Hematopoietic fingerprints: an expression database of stem cells and their progeny. Cell Stem Cell. 2007;1(5):578–91. Scholar
  29. 29.
    Bartolomei MS, Zemel S, Tilghman SM. Parental imprinting of the mouse H19 gene. Nature. 1991;351(6322):153–5. Scholar
  30. 30.
    Schwarzer A, Emmrich S, Schmidt F, Beck D, Ng M, Reimer C, et al. The non-coding RNA landscape of human hematopoiesis and leukemia. Nat Commun. 2017;8(1):218. Scholar
  31. 31.
    •• Paralkar VR, Mishra T, Luan J, Yao Y, Kossenkov AV, Anderson SM, et al. Lineage and species-specific long noncoding RNAs during erythro-megakaryocytic development. Blood. 2014;123(12):1927–37. Analysis and verification of functional lncRNAs in erythropoietic lineage development and confirmed the identity of erythro-lineage specific lncRNAs. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    • Casero D, Sandoval S, Seet CS, Scholes J, Zhu Y, Ha VL, et al. Long non-coding RNA profiling of human lymphoid progenitor cells reveals transcriptional divergence of B cell and T cell lineages. Nat Immunol. 2015;16(12):1282–91. Distinct profiles of lncRNA landscape in B and T cells. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol. 2005;5(6):472–84. Scholar
  34. 34.
    Spurlock CF 3rd, Tossberg JT, Guo Y, Collier SP, Crooke PS 3rd, Aune TM. Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat Commun. 2015;6:6932. Scholar
  35. 35.
    Brazao TF, Johnson JS, Muller J, Heger A, Ponting CP, Tybulewicz VL. Long noncoding RNAs in B-cell development and activation. Blood. 2016;128(7):e10–9. Scholar
  36. 36.
    Syrett CM, Sindhava V, Hodawadekar S, Myles A, Liang G, Zhang Y, et al. Loss of Xist RNA from the inactive X during B cell development is restored in a dynamic YY1-dependent two-step process in activated B cells. PLoS Genet. 2017;13(10):e1007050. Scholar
  37. 37.
    Delas MJ, Sabin LR, Dolzhenko E, Knott SR, Munera Maravilla E, Jackson BT, et al. lncRNA requirements for mouse acute myeloid leukemia and normal differentiation. elife. 2017;6
  38. 38.
    Tosello V, Ferrando AA. The NOTCH signaling pathway: role in the pathogenesis of T-cell acute lymphoblastic leukemia and implication for therapy. Ther Adv Hematol. 2013;4(3):199–210. Scholar
  39. 39.
    Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev. 2004;14(1):48–54. Scholar
  40. 40.
    Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A, et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell. 2014;158(3):593–606. Scholar
  41. 41.
    Sun J, Li W, Sun Y, Yu D, Wen X, Wang H, et al. A novel antisense long noncoding RNA within the IGF1R gene locus is imprinted in hematopoietic malignancies. Nucleic Acids Res. 2014;42(15):9588–601. Scholar
  42. 42.
    Alvarez-Dominguez JR, Hu W, Gromatzky AA, Lodish HF. Long noncoding RNAs during normal and malignant hematopoiesis. Int J Hematol. 2014;99(5):531–41. Scholar
  43. 43.
    Garzon R, Volinia S, Papaioannou D, Nicolet D, Kohlschmidt J, Yan PS, et al. Expression and prognostic impact of lncRNAs in acute myeloid leukemia. Proc Natl Acad Sci U S A. 2014;111(52):18679–84. Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Molecular and Cellular BiologyBeckman Research Institute at the City of HopeDuarteUSA

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