Mirnas Documented to Play a Role in Hematopoietic Cell Lineage. Our
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Table S1: miRNAs documented to play a role in hematopoietic cell lineage. Our review of the literature summarizing miRNAs known to be involved in the development and proliferation of the hematopoietic lineage cells. miRNA Expression/function/target/regulator References miR-150 Elevated during developmental stages of B and T cell maturation. 16-19 Controls B cell differentiation, present in mature, resting T and B cells but decreased upon activation of naïve T or B cells. Plays a role in establishing lymphocyte identity. Very little is known about function in T cells. Regulators: Foxp3 Target: C-Myb miR-146a/b Upregulated in macropgahe inflammatory response. Differentially 17, 20 upregulated in murine Th1 subset but abolished in Th2 subset. Upregulated in response to TCRs stimulation, as well as by IL-1 and TNF. Highly expressed in murine T-regs and could play a role in establishing lymphocyte identity. Modulates activation induced cell death in activated T cells. Negative regulator of TLR and cytokine signaling pathway. Endotoxin tolerance. Antiviral role. Targets: IRAK1, IRAK2, TRAF6, FAF1 miR-16-1 Promote apoptosis by targeting Bcl2 expression, act as tumor 22 cluster suppressor RNAs. May block differentiation of later stage hematopoietic progenitor cells to mature cells. Downregulated in CLL. Target: BCL2. miR-155 Regulator of T and B cell maturation and innate immune response. 23-29 Expressed in primary mediastinal B-cell lymphoma, T and B cells, macrophages and DCs. Upregulated during B cell activation. Involved in T cell differentiation and indicated as a positive regulator of cytokine production. Activated by stimulating TLR3 and INFab receptors in bone derived macrophages (regulation of antimicrobial defense). Associated with EBV latency type-III infection. Targets: AGTR1, PU.1, c-Maf. SHIP1, AID, SOSC1, BACH1, CEBPB, CSFR, TAB2, MAF, JARID2 Regulators: FOXP3 in Tregs, C-MYC in B cells, AP-1 and NF-kB miR-17-92 Consists of miR-17, -18a, -19a, -20a, -19b-1,–92-1, and 106a. 30-33 cluster: Over-expressed in lymphomas and other hematological miR-17 malignancies, suppress cell death, increase lymphogenesis, miR-18a regulator of T and B cell development, inhibit monocyte miR-19a proliferation, differentiation and maturation. miR-20a Targets: E2F1, BIM, PTEN, IL10 miR-19b Regulator: C-MYC miR-92a miR-106a miR-32 Direct negative effect on replication of PFV-1 virus by 21 downregulating of replication-essential viral proteins encoded by ORF2 miR-132 CREB-responsive gene that regulates neuronal outgrowth in rats by 34-35 controlling p250GAP protein expression. Endotoxin-responsive gene, LPS signaling. Differentially unregulated in six solid cancer types. Megakaryocytic differentiation miR-181a B and T cell Hematopoiesis. Positive regulator for B cell 36-37 differentiation, tentative negative T cell development regulator. Regulates sensitivity of T-cell Receptor, regulates T cell selection during thymic development, present in immature thymocytes. Changes in miR-181a levels might function as a rheostat by regulating protein phosphorylation levels. Targets:TCL1, HOXA11, DUSP5, DUSP6, SHP2 and PTPN22 miR-181b Implicated in regulation of B cell function by affecting class- 38 switching recombination miR-181c Human activated CD4(+) T lymphocytes increase IL-2 expression 39 by downregulating microRNA-181c. miR-181c was proven to have the potential to regulate CD4(+) T cell activation. miR-181c was downregulated in the process of CD4(+) T cell activation, can bind to the IL-2 3' UTR and repress its expression by inhibiting translation. Moreover, miR-181c mimics reduced activated CD4(+) T cell proliferation. miR-142 Early hematopoietic development, T-cell lineage, translocated in 40-41, 18 miR-142-3p B-PLL patients. Expressed in Tregs, repressed by FOXP3, leading to increased production of cyclic AMP and suppressor function of T-reg cells. Target: AC9 miR-223 Expression in T-lineage cells, negative regulator of neutrophil 41-43 proliferation and activation, enhances T cell differentiation. Targets: Mef2c, IGFR Regulators: PU.1, C/EBP alpha, NFI-A miR-221 Highly-expressed in human cord-blood derived hematopoietic 44-45 miR-222 CD34+ progenitor cells. Down regulated in response to erythroid lineage differentiation. Controls terminal stages in hematopoietic development. Target: c-kit miR-214 Targets Pten in activated murine T cells and its expression leads to 46 increased T cell proliferation in mice. Furthermore, upregulation of miR-214 was dependent on CD28 costimulation Target: Pten miR-24 miR-24 is consistently upregulated during terminal differentiation 47 of hematopoietic cell lines into a variety of lineages, miR-24 is also upregulated during thymic development to naive CD8 T cells. miR-103 Block differentiation of hematopoietic stem-progenitor cells 48 miR-107 (HSPC) at a later stage in HSPC development miR-29 Linked with aggressive CLL phenotype. 49 Target: TCL1 miR-LET-7e Upregulated in APL patients upon retinoic acid treatment 50 mIR-342 miR-130a Megakaryocytic differentiation. 50 Target: MAFB miR-21 Upregulated during macrophage inflammatory response. MiR-21 51-53 miR-147 upregulated in CD4+ T cells upon IL-21 stimulation and regulated miR-9 by STAT3. In peripheral human monocytes and neutrophils miR-9 is similarly upregulated by pro-inflammatory signals. Target: BCL2 miR-144 Direct targets of the critical hematopoietic transcription factor 54 miR-451 GATA-1. Required for erythropoiesis miR-129 Targets genes related to miRNAs processing or transcription 55 regulation miR-520h May promote differentiation of HSCs into progenitor cells by 55 inhibiting ABCG2 expression miR-125b Expressed in centroblasts and shown to repress PRDM1 and IRF4 55 miR-125b-1 Involved in translocation in B-ALL case 56 miR-122 Required for hepatitis C proliferation in liver 57 miR-10 miR-196b is regulated by the HSC transcription factor family 58-60 miR-196b mixed lineage leukaemia (MLL), and has a functional role in miR-126 modulating HSC homeostasis and lineage commitment, could directly repress HOX family expression, important roles in regulating HSC homeostasis. miR-126 has also been shown to regulate expression of HOXA9 and PLK2 miR-326 Expressed in T cells, promotes TH17 cell development both in 61 vitro and in vivo by targeting ETS1 miR-101 Differentially expressed in human naive, memory and TFH CD4+ 62-63 cells and inversely correlates to ICOS expression in these subsets, with the highest levels found in naive (ICOSneg) cells, intermediate levels in memory cells (ICOSint) and lowest levels in TFH cells (ICOShigh) miR-184 Inhibits NFAT1 protein expression elicited by UCB CD4+ T cells. 64 Endogenous expression of miR-184 in UCB is 58.4-fold higher compared with AB CD4+ T cells, and miR-184 blocks production of NFAT1 protein through its complementary target sequence on the NFATc2 mRNA without transcript degradation. avg-T0 log2_fold- fold- rawp- adjp- Symbol Ensembl_gene Definition log2 avg-T48 log2 T48_vs_T0 T48_vs_T0 T48_vs_T0 T48_vs_T0 ANOVA-rawp ANOVA-adjp largest fold #Mirs Mir List (includes only miRs upregulated as determined by t-test) Proto-oncogene protein c-fos (Cellular oncogene fos)(G0/G1 switch FOS ENSG00000170345 regulatory protein 7) [Source:UniProtKB/Swiss-Prot;Acc:P01100] 10.24 6.08 -4.16 -17.86 4.87E-15 5.13E-12 4.58E-28 4.10E-24 4.69 2 hsa-miR-155,hsa-miR-221, Dual specificity protein phosphatase 1 (EC 3.1.3.48)(EC 3.1.3.16)(MAP kinase phosphatase 1)(MKP-1)(Protein-tyrosine phosphatase CL100)(Dual specificity protein phosphatase hVH1) DUSP1 ENSG00000120129 [Source:UniProtKB/Swiss-Prot;Acc:P28562] 10.79 7.09 -3.70 -13.03 2.72E-11 4.94E-09 2.91E-21 2.54E-18 4.32 1 hsa-miR-200b, Protein fosB (G0/G1 switch regulatory protein 3) FOSB ENSG00000125740 [Source:UniProtKB/Swiss-Prot;Acc:P53539] 9.00 6.04 -2.96 -7.79 3.22E-14 2.31E-11 1.84E-26 1.10E-22 3.36 1 hsa-miR-27a, Integrin alpha-6 Precursor (VLA-6)(CD49 antigen-like family member F)(CD49f antigen) [Contains Integrin alpha-6 heavy chain;Integrin ITGA6 ENSG00000091409 alpha-6 light chain] [Source:UniProtKB/Swiss-Prot;Acc:P23229] 7.94 5.09 -2.85 -7.20 1.15E-08 6.54E-07 3.42E-15 3.26E-13 3.25 2 hsa-miR-19a,hsa-miR-29b, Krueppel-like factor 3 (Basic krueppel-like factor)(CACCC-box- binding protein BKLF)(TEF-2) [Source:UniProtKB/Swiss- hsa-miR-130b,hsa-miR-132,hsa-miR-135b,hsa-miR-155,hsa-miR-20a,hsa-miR- KLF3 ENSG00000109787 Prot;Acc:P57682] 8.69 6.02 -2.67 -6.38 3.50E-09 2.46E-07 3.67E-16 4.61E-14 2.87 9 218,hsa-miR-221,hsa-miR-27a,hsa-miR-365, Nuclear receptor subfamily 4 group A member 2 (Orphan nuclear receptor NURR1)(Immediate-early response protein NOT)(Transcriptionally-inducible nuclear receptor) NR4A2 ENSG00000153234 [Source:UniProtKB/Swiss-Prot;Acc:P43354] 9.57 7.04 -2.53 -5.77 2.88E-07 8.90E-06 9.78E-14 6.06E-12 3.31 4 hsa-miR-132,hsa-miR-200b,hsa-miR-206,hsa-miR-365, V-set and immunoglobulin domain-containing protein 1 Precursor (Cell surface A33 antigen)(Glycoprotein A34) VSIG1 ENSG00000101842 [Source:UniProtKB/Swiss-Prot;Acc:Q86XK7] 6.69 4.20 -2.50 -5.64 2.16E-07 7.08E-06 1.69E-15 1.73E-13 2.89 2 hsa-miR-155,hsa-miR-365, Thioredoxin-interacting protein (Vitamin D3 up-regulated protein 1)(Thioredoxin-binding protein 2) [Source:UniProtKB/Swiss- TXNIP ENSG00000117289 Prot;Acc:Q9H3M7] 10.18 7.70 -2.48 -5.56 8.44E-08 3.26E-06 5.01E-13 2.47E-11 2.77 1 hsa-miR-18a, Cytochrome b-245 heavy chain (EC 1.-.-.-)(p22 phagocyte B- cytochrome)(Neutrophil cytochrome b 91 kDa polypeptide)(Heme- binding membrane glycoprotein gp91phox)(CGD91-phox)(gp91- phox)(gp91-1)(Cytochrome b(558)