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. 2011 May;21(5):798-810.
doi: 10.1101/gr.111385.110. Epub 2011 Mar 30.

MicroRNA programs in normal and aberrant stem and progenitor cells

Christopher P Arnold  1 , Ruoying Tan, Baiyu Zhou, Si-Biao Yue, Steven Schaffert, Joseph R Biggs, Regis Doyonnas, Miao-Chia Lo, John M Perry, Valérie M Renault, Alessandra Sacco, Tim Somervaille, Patrick Viatour, Anne Brunet, Michael L Cleary, Linheng Li, Julien Sage, Dong-Er Zhang, Helen M Blau, Caifu Chen, Chang-Zheng Chen
Affiliations

MicroRNA programs in normal and aberrant stem and progenitor cells

Christopher P Arnold et al. Genome Res. 2011 May.

Abstract

Emerging evidence suggests that microRNAs (miRNAs), an abundant class of ∼22-nucleotide small regulatory RNAs, play key roles in controlling the post-transcriptional genetic programs in stem and progenitor cells. Here we systematically examined miRNA expression profiles in various adult tissue-specific stem cells and their differentiated counterparts. These analyses revealed miRNA programs that are common or unique to blood, muscle, and neural stem cell populations and miRNA signatures that mark the transitions from self-renewing and quiescent stem cells to proliferative and differentiating progenitor cells. Moreover, we identified a stem/progenitor transition miRNA (SPT-miRNA) signature that predicts the effects of genetic perturbations, such as loss of PTEN and the Rb family, AML1-ETO9a expression, and MLL-AF10 transformation, on self-renewal and proliferation potentials of mutant stem/progenitor cells. We showed that some of the SPT-miRNAs control the self-renewal of embryonic stem cells and the reconstitution potential of hematopoietic stem cells (HSCs). Finally, we demonstrated that SPT-miRNAs coordinately regulate genes that are known to play roles in controlling HSC self-renewal, such as Hoxb6 and Hoxa4. Together, these analyses reveal the miRNA programs that may control key processes in normal and aberrant stem and progenitor cells, setting the foundations for dissecting post-transcriptional regulatory networks in stem cells.

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Figures

Figure 1.
Figure 1.
Principal component analyses indicating the relative distances between the miRNA profiles of various stem and progenitor cell populations.
Figure 2.
Figure 2.
Identification of tissue-specific stem cell–related miRNA signatures. (A) Schematic diagrams illustrate the comparisons made to reveal the tissue-specific SC-related miRNA signatures: I, miRNAs enriched in LT-HSCs (LT-HSC miRNAs); II, miRNAs enriched in NSPCs (NSPC miRNAs); III, miRNAs enriched in MuSCs (MuSC miRNAs); and IV, the common SC miRNA signatures (SC-related miRNAs). They are depicted as the single-colored regions (I, II, III) and a triple-colored region (IV) in the Venn diagram. (B) Heatmaps depicting common and tissue-specific miRNAs derived from KMC analyses. A false color scale was used to indicate normalized arbitrary expression intensity (ΔCt) with “−5” for the lowest expression, “0” for median expression, and “5” for the highest expression.
Figure 3.
Figure 3.
miRNAs differentially expressed in LT-HSCs and KSL cells and in MuSCs and myoblasts. (A) Schematic diagram depicting the comparisons made to reveal miRNAs that are expressed in LT-HSCs only (I), expressed in KSL cells only (II), or highly expressed in both (III). SAM analyses were carried out to identify miRNAs that were significantly different or unchanged between LT-HSCs and KSL cells (FDR < 0.001), which were then further classified by KMC analyses as depicted in heatmaps. A false color scale was used to indicate the normalized arbitrary expression intensity (ΔCt). (B) Fold changes in the top 69 miRNAs that differed significantly between LT-HSCs and KSL cells (SAM, FDR < 0.001) are shown (Log2 Fold [LT-HSC/KSL]). (C) Schematic diagram depicting the comparisons made to reveal miRNAs that are expressed in MuSCs only (I), expressed in myoblasts only (II), or highly expressed in both (III). SAM analyses were carried out to identify miRNAs that were significantly different or unchanged between MuSCs and myoblasts (FDR < 0.001), which were then further classified by KMC analyses as depicted in heatmaps. A false color scale was used to indicate the normalized arbitrary expression intensity (ΔCt). (D) Fold changes in the top 69 miRNAs that differed significantly between MuSCs and myoblasts (SAM, FDR < 0.001) are shown (Log2 Fold[MuSC/myoblasts]). Selected miRNAs or groups of miRNA are color-coded. The miR-181 family miRNA consists of miR-181a, miR-181b, miR-181c, and miR-181d. The miR-17-92 family miRNA clusters consist of miR-17-92, miR-106b-25, and miR-106a-363. The let-7 family consists of let-7a-i.
Figure 4.
Figure 4.
miRNA programs underlie the stem to progenitor transition. Multi-factorial analyses revealed various miRNA programs that control the transitions from blood and muscle stem cells (LT-HSCs and MuSCs) to the corresponding immediate differentiating progenies (KSL cells and myoblasts, respectively). (A) The comparisons performed in multi-factorial analyses to yield functional miRNA groups identified. (B) miRNAs discordantly regulated during stem to progenitor transition in blood and muscle. (C,D) miRNAs concordantly regulated during stem to progenitor transition but more drastically regulated in either muscle (C) or blood (D). (E) miRNAs concordantly regulated during stem to progenitor transition in blood and muscle.
Figure 5.
Figure 5.
Dysregulation of miRNA programs by genetic mutations altering the functional properties of stem/progenitor cells. Global changes of miRNA expression in mutant stem and progenitor cells: (A) KSL-ETO, (B) KSL-RbTKO, (C) KSL-PTEN, and (D) MLL-LSC. miRNAs that are significantly different between mutant cells and their control cells (SAM, FDR < 0.001) are shown as fold of changes (Log2 Fold Mutant/Control). Heatmaps depict the specific miRNA clusters that were turned on/off in mutant stem and/or progenitor cells: (E) KSL-ETO; (F) KSL-RbTKO; (G) KSL-PTEN; and (H) MLL-LSC. False color scales were used to indicate normalized expression intensity.
Figure 6.
Figure 6.
A stem/progenitor transition miRNA signature predicts the functional properties of mutant stem/progenitor cells. (A) A stem/progenitor transition miRNA signature that is predictive of stem or progenitor identity/property of mutant stem/progenitor cells was identified from the miRNAs that were concordantly regulated during stem to progenitor transition in muscle and blood by using PAM analyses (FDR < 0.001). Hierarchical clustering analyses showed that the 12 stem/progenitor transition miRNAs predict the functional properties of mutant stem/progenitor cells: (B) KSL-PTEN; (C) KSL-ETO; (D) KSL-RbTKO; and (E) MLL-LSC. False color scale depicts relative changes in expression.
Figure 7.
Figure 7.
Effects of SPT-miRNAs on ES cell self-renewal and HSC reconstitution. (A) Schematics depicting a competition assay for examining the effects of miRNAs on ES cell self-renewal. (B,C) Relative ratios of miRNA-infected ES cells in a competition assay (n = 3, mean ± SD). (D) Schematics depicting a competition assay for examining the effects of miRNAs on HSC reconstitution. Vector-specific TaqMan qPCR primers and probes were used to determine the relative levels of the miRNA viral integrations relative to that of control viral vector integration. (E) Relative ratios of miRNA-infected cells in a competitive bone marrow transplantation assay (n = 5). Results from individual recipients at various time points (within 5%–95% distribution) after transplantation are shown, and median values of all recipients (horizontal lines) are indicated.
Figure 8.
Figure 8.
Coordinated regulation of Hox UTRs by the SPT-miRNAs. (A) Schematic diagrams of predicted target sites of SPT-miRNAs on Hoxb6, Hoxa4, and Hoxd13. Repression of luciferase reporters bearing UTRs from Hoxb6 (B), Hoxa4 (C), or Hoxd13 (D) by the SPT-miRNAs and corresponding seed mutant controls (sm) (n = 3, mean ± SD, two-tailed, type 2, Student t-test, compared to the control vector, N.S. for p > 0.05). (E) Model of SPT-miRNA regulation of Hox genes during the stem to progenitor transition and corresponding changes in self-renewal and proliferation potentials.
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