Journal of Hematology Blood Transfusion & Disorders Category: Clinical Type: Research Article

Ingenuity Pathway Analysis of miRnas and mRNAs in Stored Platelets Identifies the Potential of miRNAs in Regulating Platelet Functions Relevant to Storage Lesions

Chintamani D Atreya1*, Neetu Dahiya2 and Sandhya Kulkarni2
1 Division of hematology, Section of Cell Biology, Laboratory of Cellular Hematology, US Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Ave, Silver Spring, MD 20993, United states
2 Division of hematology, Section of Cell Biology, Laboratory of Cellular Hematology, US Food and Drug Administration, Center for Biologics Evaluation and Research, United states

*Corresponding Author(s):
Chintamani D Atreya
Division Of Hematology, Section Of Cell Biology, Laboratory Of Cellular Hematology, US Food And Drug Administration, Center For Biologics Evaluation And Research, 10903 New Hampshire Ave, Silver Spring, MD 20993, United States
Tel:+1 240-402-8009,
Email:chintamani.atreya@fda.hhs.gov

Received Date: Sep 27, 2016
Accepted Date: Dec 03, 2016
Published Date: Dec 19, 2016
DOI:10.24966/HBTD-2999/100012

Abstract

Under blood bank storage conditions platelets undergo physiological changes leading to storage lesions that affect platelet quality. Since small noncoding micrornas (miRNAs) are posttranslational regulators of cellular mRNA expression, we envisioned that miRNA targeting of mRNAs cause perturbations in stored platelets and affect their quality. In this report, differential miRNA and mRNA microarray data on day 0, day 5 and day 9 stored human platelet samples were analyzed. The analysis identified 7 upregulated miRNAs (miR-320b, miR-1-3p, miR-214-3p, miR-197-3p, miR-129-5p, miR-183-5p and miR-292b-5p) that are known to regulate 35 mRNAs. The analysis further identified 68 differentially expressed miRNAs common to day 5 and day 9 of storage (p-value <0.05). Ingenuity Pathway Analysis (IPA) based search for mRNAs that are potentially regulated by these miRNAs identified 17 mRNAs involved in platelet activation, 28 mRNAs associated with platelet aggregation, 12 mRNAs affecting platelet binding and 9 mRNAs involved in adhesion as well as 27 mRNAs implicated in cellular apoptosis. The IPA also assisted in identifying top 5 signaling pathways and network functions of platelets in storage. The results clearly identify the potential of miRNAs in regulating functions relevant to the platelet storage lesions, which provides a basis for further experimental verification.

Keywords

Ingenuity pathway analysis; microarray; miRNA; Networks; Platelets; Signaling pathway

INTRODUCTION

Platelets (PLTs) are one of the most important life-saving transfusion products. During storage under standard blood bank conditions, platelets start to lose their viability with time and as a consequence, platelets do undergo morphological and physiological changes during storage collectively known as Platelet Storage Lesion (PSL), which negatively impact their performance following transfusion.

MicroRNAs (miRNAs) are a type of small non-coding RNAs involved in posttranscriptional regulation of the genes (mRNAs) that they target. Role of miRNAs in platelets biosynthesis and presence of an active post-transcriptional miRNA mediated mRNA regulation has already been reported [1]. In addition, a number of platelet originated miRNAs have also been identified as possible disease biomarkers [2,3]. Platelets also release microparticles packed with miRNA-Ago2 RISC machinery capable of regulating gene expression and phenotype of the recipient cells [4,5]. More recently, Rowley et al., [6] reported the effect of miRNA processing on platelet functions using a Dicer1 deficient murine model. All these studies suggest that miRNAs play a role in platelet biology. However, none of these studies address whether perturbations in miRNAs and Messenger RNAs (mRNAs) do occur in platelets stored under blood bank conditions for transfusion, and the consequences of these perturbations on the quality of stored platelets.

Due to PSL development, both structure and some of the functions of platelets are compromised during storage. Our goal is to identify potential miRNA:mRNA interactions that are consequential to these changes. We have generated both miRNA and mRNA differential profiles and part of the data was reported [7,8] and further analysis of this data constitutes present report. Here in this analysis, we performed a) IPA “MicroRNA target filter” tool to extract a list of potential miRNA-targeted mRNAs of stored platelets and, b) IPA “Core analysis” (In-silico analysis) to identify the potential functions of these mRNAs in stored platelets. Overall, this bioinformatics-based approach demonstrates that platelet miRNAs are capable of regulating mRNA functions relevant to PSL and provides confidence to the field to test each of these potential miRNA:mRNA interactions in the context of platelet storage quality towards improving the quality of platelets in storage.

METHODS

Platelet samples and storage

Platelets samples collected from healthy donors at National Institutes of Health (NIH) blood bank were stored at 22°C in platelet shaker. The IRB approval for this study was exempted under FDA-RIHSC approved protocol #03-120B. Samples were collected from the bag on day 0, day 5 and day 9 of storage and leukocyte-reduced by using CD45 conjugated beads (Dynabeads, Life Technologies, Carlsbad, CA, USA) and samples were stored at -80°C.

RNA extraction, quantification and quality assessment

Total RNA was extracted using TRIZOL as per manufacturer’s instruction (Life Technologies). Amount of RNA in each sample was quantified using NanoVue GE (GE, Pittsburgh, PA, USA) and quality of RNA samples were determined by gel-on-chip analysis using Agilent bioanalyzer.

Microarrays and RT-qPCR

MicroRNA profiling was performed using Affymetrix Gene chip miRNA 3.0 arrays. Samples collected from 4 different donors at three different time points were used for microRNA microarrays. For each array, 300 ng of total RNA was used for performing the experiment. The mRNA profiling was done using HumanRef-8 Expression BeadChip (Illumina, Inc., San Diego, CA, USA) microarrays. Total RNAs extracted from two independent donors at three different storage time points were used for the profiling. RT-qPCR was done using TaqMan MicroRNA assays (Applied Biosystems, Foster City, CA, USA).

MiRNA target filter analysis

The detailed protocol for total RNA extraction from platelets stored for up to 9 days, miRNA and mRNA arrays and RT-qPCR are all as described previously [8]. Using microarrays, the differentially expressed miRNAs (fold cut off >1.5, p-value <0.05) and mRNA (fold cut off >1.5, p-value <0.05) during storage were identified. “MicroRNA target filter” function was applied in our ingenuity pathway analysis tool to determine potential targets of miRNAs differentially expressed on day 5 and day 9 compared to day 0. The list of potential miRNA targets (i.e., mRNAs) compiled by IPA includes target genes predicted by different algorithms such as miRecords, target scan and experimental targets listed in tarbase (a database of experimental targets) and identified by Ingenuity Knowledge Base. The “MicroRNA target filter” tools provide a unique opportunity to find miRNA targets relevant to the biological context of interest (by performing miRNA and mRNAs profiling of the same samples) which can be very helpful in overcoming the complexity of miRNA target genes.

Network functions and pathway analyses

We populated a list of miRNAs differentially expressed on both day 5 and day 9 and extracted their potential target mRNAs using IPA tool. To find the mRNAs relevant to platelets in storage, mRNAs showing significant differential expression in platelets during storage were selected. To illustrate their functional role in platelets, these target genes were analyzed using IPA “Core analysis” function. The regulatory network functions identified are presented as a graph. The genes and their functional relation are represented as nodes and lines, respectively. The color of the nodes represents their up (red color) or downregulation (green color) status and their intensity represents the degree/extent of up or downregulation. The different shapes are indicative of the nature of the molecule based on their type of activity (i.e., cytokines, enzymes etc.). The top signaling pathways and network functions of the potential mRNA target genes using IPA were also analyzed. The significance of the pathways and network functions were determined based on the number of target genes identified and p-value <0.05.

RESULTS

In our previous report [8] we found differential expression of 302 miRNAs in platelet samples during storage at 22°C (p-value <0.05). In this report, the principal component analysis of these significant miRNAs showed clear separation of samples into three distinct groups based on the days in storage (Figure 1). Of the 302 miRNAs, 68 miRNAs have shown similar expression pattern on day 5 and day 9, however the changes are more pronounced on day 9 compared to day 5 (Table 1). In order to understand the role of these differentially expressed miRNAs during storage, the mRNAs targeted for regulation by these miRNAs were determined. The mRNA profiling of two sets of the same RNA samples that were subjected to microRNA microarray profiling showed differential expression of 54 and 864 mRNAs on day 5 and day 9, respectively (Supplementary Table 1). To determine which mRNAs serve as potential targets of the differentially expressed common miRNAs, the Ingenuity Pathway Analysis tool was used. We searched for miRNA:mRNA pairs showing opposite expression pattern on different days of storage. The analysis resulted in identification of 1788 miRNA:mRNA pairs involving 59 miRNAs and 605 mRNAs showing negative correlation (Supplementary Table 2).

 

Figure 1: Principal Component Analysis (PCA) of platelet miRNAs differentially expressed (p<0.05) on day 5 and day 9 of storage, compared to day 0.

 

MiRNA Name p-value p-value Fold-Change (Day 5 vs. Day 0) Fold-Change (Day 9 vs. Day 0)
(Day 5 vs. Day 0) (Day 9 vs. Day 0)
hsa-miR-1224-5p 0.025 0.004 3 5.1
hsa-miR-1225-5p 0.014 0.003 4.6 7.7
hsa-miR-1226 0.017 0.011 1.7 1.8
hsa-miR-1231 0.015 0.003 9 24.4
hsa-miR-1254 0.01 0.005 3.4 4.2
hsa-miR-125b-1* 0.011 0.001 4.7 14.1
hsa-miR-1270 0.012 0 1.5 2.1
hsa-miR-1275 0.013 0 2.8 9
hsa-miR-1287 0.023 0.045 1.6 1.5
hsa-miR-1292 0.026 0.008 2.5 3.5
hsa-miR-1304 0.046 0 1.6 3.6
hsa-miR-1469 0.042 0.009 3.5 6.5
hsa-miR-149* 0.034 0.004 3.6 8.2
hsa-miR-150* 0.039 0.001 3.1 13
hsa-miR-1538 0.034 0.009 1.5 1.8
hsa-miR-188-3p 0.008 0.006 -1.5 -1.5
hsa-miR-1909* 0.019 0.001 2.2 4.2
hsa-miR-193a-5p 0.051 0.011 3.3 6
hsa-miR-197 0.015 0.002 1.5 1.9
hsa-miR-202* 0.022 0.001 -1.7 -2.8
hsa-miR-2276 0.045 0.012 2 2.8
hsa-miR-23a* 0.009 0.001 1.6 2.2
hsa-miR-3064-5p 0.019 0.001 1.9 3.1
hsa-miR-31 0.028 0.034 -1.9 -1.8
hsa-miR-3162-5p 0.006 0.001 2.6 3.7
hsa-miR-3163 0.033 0.003 -1.6 -2.2
hsa-miR-3177-3p 0.028 0.01 2 2.5
hsa-miR-3185 0.034 0.007 4.6 9.5
hsa-miR-3187-3p 0.046 0.004 3.3 8.6
hsa-miR-3195 0.043 0.002 2.8 9
hsa-miR-3605-5p 0.023 0 1.6 3
hsa-miR-3646 0.005 0.002 1.5 1.7
hsa-miR-3663-3p 0.024 0.003 6.4 18.1
hsa-miR-3679-5p 0.029 0.003 2.6 5.1
hsa-miR-377* 0.026 0.02 1.6 1.7
hsa-miR-3927 0.041 0.001 -1.6 -2.8
hsa-miR-3940-5p 0.048 0.008 3 5.7
hsa-miR-432* 0.018 0.015 1.6 1.6
hsa-miR-4462 0.053 0.011 2.5 3.9
hsa-miR-4463 0.039 0.005 3 5.8
hsa-miR-4486 0.026 0.003 5 14.8
hsa-miR-4516 0.034 0.014 3.6 4.9
hsa-miR-4523 0.001 0 1.6 2.2
hsa-miR-4530 0.029 0.009 3.3 5
hsa-miR-4532 0.007 0.001 6.8 24.9
hsa-miR-4651 0.03 0.01 3.7 5.7
hsa-miR-4674 0.026 0.003 4.2 10.2
hsa-miR-4689 0.026 0.014 5 6.5
hsa-miR-4695-5p 0.02 0.003 3.4 6.3
hsa-miR-4707-5p 0.025 0.006 4.1 7
hsa-miR-4734 0.03 0.009 4.2 6.9
hsa-miR-4741 0.016 0.005 5.4 8.8
hsa-miR-4745-5p 0.023 0.006 4 6.8
hsa-miR-4791 0.01 0.003 -2.6 -3.4
hsa-miR-509-3-5p 0.045 0.001 -1.5 -2.3
hsa-miR-510 0.022 0.006 -1.8 -2.2
hsa-miR-542-3p 0.039 0.022 -2.1 -2.4
hsa-miR-548a-3p 0.001 0 -1.5 -2.6
hsa-miR-548aa 0.016 0 -1.6 -2.6
hsa-miR-548ac 0.042 0.001 -1.6 -3.1
hsa-miR-548ae 0.052 0.009 -1.8 -2.5
hsa-miR-548al 0.043 0.042 -2.1 -2.1
hsa-miR-602 0.054 0.003 3.3 10.3
hsa-miR-603 0.036 0.004 -1.8 -2.7
hsa-miR-635 0.033 0.014 -2.1 -2.4
hsa-miR-642b 0.004 0.001 4.4 6
hsa-miR-650 0.049 0.044 1.5 1.5
hsa-miR-943 0.03 0.001 1.6 2.5

Table 1: List of 68 differentially expressed miRNAs common to day 5 and day 9 storage (p-value <0.05).

 

miRNA name p-value Fold Change Source Confidence Symbol False Discovery Rate (q-value) Fold Change Pathway
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) AFAP1 0.000 -4.990  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) ANKRD28 0.001 -1.900  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) BTBD11 0.000 -6.920  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human High (predicted), Moderate (predicted) CARD8 0.000 -1.640  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) DSTN 0.037 -1.470  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) GATA2 0.008 -1.630 Thrombin Signaling
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) MAP2K3 0.047 -1.550 Acute Myeloid Leukemia Signaling, Acute Phase Response Signaling, AMPK Signaling, B Cell Receptor Signaling, Cardiac Hypertrophy Signaling, CD27 Signaling in Lymphocytes, CD40 Signaling, Cholecystokinin/Gastrin-mediated Signaling, ErbB Signaling, Fc Epsilon RI Signaling, FGF Signaling, Germ Cell-Sertoli Cell Junction Signaling, GNRH Signaling, HMGB1 Signaling, IL-1 Signaling, IL-10 Signaling, IL-17 Signaling, IL-6 Signaling, LPS-stimulated MAPK Signaling, Melatonin Signaling, Molecular Mechanisms of Cancer, Neurotrophin/TRK Signaling, NRF2-mediated Oxidative Stress Response, p38 MAPK Signaling, PPARα/RXRα Activation, Pyridoxal 5'-phosphate Salvage Pathway, Regulation of the Epithelial-Mesenchymal Transition Pathway, Role of IL-17A in Arthritis, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis, Role of MAPK Signaling in the Pathogenesis of Influenza, Role of NFAT in Cardiac Hypertrophy, Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis, Role of PKR in Interferon Induction and Antiviral Response, Salvage Pathways of Pyrimidine Ribonucleotides, Sertoli Cell-Sertoli Cell Junction Signaling, TGF-β Signaling, Toll-like Receptor Signaling, Type I Diabetes Mellitus Signaling, Xenobiotic Metabolism Signaling
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) PROSER2 0.000 -2.530  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) RGS6 0.000 -1.580  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) SLC2A3 0.002 -9.910 Antioxidant Action of Vitamin C, HIF1α Signaling, Vitamin-C Transport
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) STK4 0.000 -5.670 HIPPO signaling, Non-Small Cell Lung Cancer Signaling
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) TMCC2 0.000 -3.300  
hsa-miR-3679-5p 0.003 5.100 TargetScan Human Moderate (predicted) VPS41 0.010 -2.660 autophagy, phagosome maturation
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) BICD2 0.027 -7.190  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) C1orf198 0.001 -7.420  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) CBL 0.000 -1.740 14-3-3-mediated Signaling, Clathrin-mediated Endocytosis Signaling, Ephrin B Signaling, Erythropoietin Signaling, Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes, FLT3 Signaling in Hematopoietic Progenitor Cells, Insulin Receptor Signaling, Molecular Mechanisms of Cancer, PI3K Signaling in B Lymphocytes, Protein Ubiquitination Pathway, PTEN Signaling, RANK Signaling in Osteoclasts, Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis, Systemic Lupus Erythematosus Signaling, T Cell Receptor Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) DENND3 0.000 -1.540  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) DYRK1A 0.000 -1.450 Pyridoxal 5'-phosphate Salvage Pathway, Salvage Pathways of Pyrimidine Ribonucleotides, Sonic Hedgehog Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) FNBP1 0.000 -1.530 Actin Nucleation by ARP-WASP Complex, Cardiac Hypertrophy Signaling, Cholecystokinin/Gastrin-mediated Signaling, Colorectal Cancer Metastasis Signaling, CXCR4 Signaling, Germ Cell-Sertoli Cell Junction Signaling, Glioblastoma Multiforme Signaling, Glioma Invasiveness Signaling, Gαq Signaling, HMGB1 Signaling, IL-8 Signaling, ILK Signaling, Integrin Signaling, Molecular Mechanisms of Cancer, mTOR Signaling, phagosome formation, Phospholipase C Signaling, Production of Nitric Oxide and Reactive Oxygen Species in Macrophages, Regulation of Actin-based Motility by Rho, RhoGDI Signaling, Semaphorin Signaling in Neurons, Signaling by Rho Family GTPases, Sphingosine-1-phosphate Signaling, Tec Kinase Signaling, Thrombin Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) GDE1 0.018 -2.620  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) GTDC1 0.000 -1.570  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) H3F3A/H3F3B 0.000 -4.180 ERK/MAPK Signaling, Estrogen Receptor Signaling, p38 MAPK Signaling, Protein Kinase A Signaling, UVB-Induced MAPK Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) HECTD4 0.000 -2.070  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human High (predicted) MADD 0.000 -5.195 TNFR1 Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) MAPK8IP3 0.000 -1.500 Reelin Signaling in Neurons, SAPK/JNK Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) MBP 0.000 -12.630  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) MID1IP1 0.000 -1.540  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) PNKD 0.000 -8.870  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) POLR1D 0.029 -2.260 Assembly of RNA Polymerase I Complex
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) RAP2A 0.000 -1.800 B Cell Receptor Signaling, Calcium Signaling, Integrin Signaling, Molecular Mechanisms of Cancer
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) SEC14L1 0.044 -3.080  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) SHKBP1 0.000 -1.530  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) SLA2 0.030 -1.900  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) SLC39A3 0.000 -2.730  
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) TLK1 0.024 -3.010 ATM Signaling, Role of CHK Proteins in Cell Cycle Checkpoint Control
hsa-miR-1224-5p 0.004 5.100 TargetScan Human High (predicted) TNS1 0.000 -2.530 FAK Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) TPP1 0.013 -5.000 Telomerase Signaling
hsa-miR-1224-5p 0.004 5.100 TargetScan Human Moderate (predicted) TTC7B 0.000 -1.550  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) ARHGAP21 0.006 -5.740  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) BCL2L2 0.000 -2.780  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) BCL7B 0.053 -1.530  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) CD47 0.003 -2.120 Inhibition of Angiogenesis by TSP1
hsa-miR-1225-5p 0.003 7.700 TargetScan Human High (predicted) CDC14B 0.000 -8.130 Protein Kinase A Signaling
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) CSK 0.000 -7.130 Actin Cytoskeleton Signaling, B Cell Receptor Signaling, CD28 Signaling in T Helper Cells, FAK Signaling, Gαq Signaling, iCOS-iCOSL Signaling in T Helper Cells, Paxillin Signaling, RAR Activation, T Cell Receptor Signaling
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) EIF4H 0.000 -2.140  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) ELMO2 0.000 -1.600 CXCR4 Signaling
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) GLG1 0.000 -1.790 Agranulocyte Adhesion and Diapedesis, Atherosclerosis Signaling, Granulocyte Adhesion and Diapedesis
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) GTDC1 0.000 -1.570  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) IRS1 0.007 -1.490 14-3-3-mediated Signaling, 3-phosphoinositide Biosynthesis, Actin Cytoskeleton Signaling, Acute Myeloid Leukemia Signaling, Aldosterone Signaling in Epithelial Cells, AMPK Signaling, Amyotrophic Lateral Sclerosis Signaling, Angiopoietin Signaling, Antiproliferative Role of Somatostatin Receptor 2, Axonal Guidance Signaling, B Cell Receptor Signaling, Breast Cancer Regulation by Stathmin1, Cardiac Hypertrophy Signaling, CCR3 Signaling in Eosinophils, CD28 Signaling in T Helper Cells, CD40 Signaling, Ceramide Signaling, Chronic Myeloid Leukemia Signaling, Clathrin-mediated Endocytosis Signaling, CNTF Signaling, Colorectal Cancer Metastasis Signaling, CREB Signaling in Neurons, CTLA4 Signaling in Cytotoxic T Lymphocytes, CXCR4 Signaling, Dendritic Cell Maturation, Docosahexaenoic Acid (DHA) Signaling, EGF Signaling, EIF2 Signaling, Endometrial Cancer Signaling, Endothelin-1 Signaling, eNOS Signaling, Ephrin A Signaling, ErbB Signaling, ErbB2-ErbB3 Signaling, ErbB4 Signaling, ERK/MAPK Signaling, Erythropoietin Signaling, Estrogen-Dependent Breast Cancer Signaling, FAK Signaling, Fc Epsilon RI Signaling, FcγRIIB Signaling in B Lymphocytes, FGF Signaling, FLT3 Signaling in Hematopoietic Progenitor Cells, fMLP Signaling in Neutrophils, G-Protein Coupled Receptor Signaling, Gap Junction Signaling, GDNF Family Ligand-Receptor Interactions, Germ Cell-Sertoli Cell Junction Signaling, Glioblastoma Multiforme Signaling, Glioma Invasiveness Signaling, Glioma Signaling, Glucocorticoid Receptor Signaling, GM-CSF Signaling, Growth Hormone Signaling, Gα12/13 Signaling, Gαq Signaling, HER-2 Signaling in Breast Cancer, Hereditary Breast Cancer Signaling, HGF Signaling, HIF1α Signaling, HMGB1 Signaling, Human Embryonic Stem Cell Pluripotency, Huntington's Disease Signaling, iCOS-iCOSL Signaling in T Helper Cells, IGF-1 Signaling, IL-12 Signaling and Production in Macrophages, IL-15 Signaling, IL-17 Signaling, IL-17A Signaling in Airway Cells, IL-2 Signaling, IL-3 Signaling, IL-4 Signaling, IL-6 Signaling, IL-8 Signaling, IL-9 Signaling, ILK Signaling, Insulin Receptor Signaling, Integrin Signaling, JAK/Stat Signaling, Leptin Signaling in Obesity, Leukocyte Extravasation Signaling, LPS-stimulated MAPK Signaling, Lymphotoxin β Receptor Signaling, Macropinocytosis Signaling, Melanocyte Development and Pigmentation Signaling, Melanoma Signaling, Molecular Mechanisms of Cancer, Mouse Embryonic Stem Cell Pluripotency, MSP-RON Signaling Pathway, mTOR Signaling, Myc Mediated Apoptosis Signaling, Natural Killer Cell Signaling, Neuropathic Pain Signaling In Dorsal Horn Neurons, Neurotrophin/TRK Signaling, NF-κB Activation by Viruses, NF-κB Signaling, NGF Signaling, Nitric Oxide Signaling in the Cardiovascular System, Non-Small Cell Lung Cancer Signaling, NRF2-mediated Oxidative Stress Response, Ovarian Cancer Signaling, P2Y Purigenic Receptor Signaling Pathway, p53 Signaling, p70S6K Signaling, PAK Signaling, Pancreatic Adenocarcinoma Signaling, Paxillin Signaling, PDGF Signaling, PEDF Signaling, phagosome formation, PI3K Signaling in B Lymphocytes, PKCθ Signaling in T Lymphocytes, PPARα/RXRα Activation, Production of Nitric Oxide and Reactive Oxygen Species in Macrophages, Prolactin Signaling, Prostate Cancer Signaling, Rac Signaling, RANK Signaling in Osteoclasts, Reelin Signaling in Neurons, Regulation of eIF4 and p70S6K Signaling, Regulation of the Epithelial-Mesenchymal Transition Pathway, Relaxin Signaling, Renal Cell Carcinoma Signaling, Renin-Angiotensin Signaling, Role of IL-17A in Arthritis, Role of JAK1 and JAK3 in γc Cytokine Signaling, Role of JAK2 in Hormone-like Cytokine Signaling, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis, Role of NANOG in Mammalian Embryonic Stem Cell Pluripotency, Role of NFAT in Cardiac Hypertrophy, Role of NFAT in Regulation of the Immune Response, Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis, Role of p14/p19ARF in Tumor Suppression, Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, Role of Tissue Factor in Cancer, SAPK/JNK Signaling, Signaling by Rho Family GTPases, Small Cell Lung Cancer Signaling, Sphingosine-1-phosphate Signaling, Superpathway of Inositol Phosphate Compounds, Systemic Lupus Erythematosus Signaling, T Cell Receptor Signaling, Tec Kinase Signaling, Telomerase Signaling, Thrombin Signaling, Thrombopoietin Signaling, TR/RXR Activation, Type II Diabetes Mellitus Signaling, UVA-Induced MAPK Signaling, UVB-Induced MAPK Signaling, VEGF Family Ligand-Receptor Interactions, VEGF Signaling, Virus Entry via Endocytic Pathways, Xenobiotic Metabolism Signaling
hsa-miR-1225-5p 0.003 7.700 TargetScan Human High (predicted) NREP 0.001 -4.180  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) PSME4 0.001 -3.180 Huntington's Disease Signaling, Polyamine Regulation in Colon Cancer
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) SEC16A 0.003 -1.470 1D-myo-inositol Hexakisphosphate Biosynthesis II (Mammalian), D-myo-inositol (1, 3, 4)-trisphosphate Biosynthesis, D-myo-inositol (1, 4, 5)-trisphosphate Degradation, Superpathway of D-myo-inositol (1, 4, 5)-trisphosphate Metabolism, Superpathway of Inositol Phosphate Compounds
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) SLMAP 0.052 -2.780  
hsa-miR-1225-5p 0.003 7.700 TargetScan Human Moderate (predicted) SYK 0.003 -4.360 B Cell Receptor Signaling, CD28 Signaling in T Helper Cells, CTLA4 Signaling in Cytotoxic T Lymphocytes, Fc Epsilon RI Signaling, Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes, FcγRIIB Signaling in B Lymphocytes, IL-15 Signaling, IL-2 Signaling, Natural Killer Cell Signaling, p70S6K Signaling, phagosome formation, Phospholipase C Signaling, PI3K Signaling in B Lymphocytes, Role of JAK1 and JAK3 in γc Cytokine Signaling, Role of NFAT in Regulation of the Immune Response, Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses
hsa-miR-1225-5p 0.003 7.700 TargetScan Human High (predicted) TAL1 0.000 -5.160  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) ADIPOR2 0.000 -3.280 PPARα/RXRα Activation, Type II Diabetes Mellitus Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human High (predicted) ATP2A2 0.002 -1.480 Calcium Signaling, Calcium Transport I, Calcium-induced T Lymphocyte Apoptosis, Cardiac β-adrenergic Signaling, Dopamine-DARPP32 Feedback in cAMP Signaling, Nitric Oxide Signaling in the Cardiovascular System
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) ATXN7L3 0.025 -2.710  
hsa-miR-1226 0.011 1.800 TargetScan Human High (predicted) B4GALT1 0.000 -1.790  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) BCR 0.000 -2.390  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) C9orf69 0.010 -2.620  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CD47 0.003 -2.120 Inhibition of Angiogenesis by TSP1
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CDR2L 0.000 -3.870  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CDS2 0.007 -1.900 CDP-diacylglycerol Biosynthesis I, Phosphatidylglycerol Biosynthesis II (Non-plastidic)
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CHMP6 0.047 -4.410 Mechanisms of Viral Exit from Host Cells
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CLCN3 0.001 -3.280  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) CTDSPL 0.000 -16.420  
hsa-miR-1226 0.011 1.800 TargetScan Human High (predicted) DAG1 0.000 -2.700 Agrin Interactions at Neuromuscular Junction, nNOS Signaling in Skeletal Muscle Cells
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) DSCR3 0.000 -2.070  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) GFOD1 0.000 -2.330  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) GRB2 0.000 -2.500 14-3-3-mediated Signaling, 3-phosphoinositide Biosynthesis, Actin Cytoskeleton Signaling, Actin Nucleation by ARP-WASP Complex, Acute Myeloid Leukemia Signaling, Acute Phase Response Signaling, Aldosterone Signaling in Epithelial Cells, AMPK Signaling, Amyotrophic Lateral Sclerosis Signaling, Angiopoietin Signaling, Antiproliferative Role of Somatostatin Receptor 2, Axonal Guidance Signaling, B Cell Receptor Signaling, BMP signaling pathway, Breast Cancer Regulation by Stathmin1, Cardiac Hypertrophy Signaling, CCR3 Signaling in Eosinophils, CD28 Signaling in T Helper Cells, CD40 Signaling, Ceramide Signaling, Cholecystokinin/Gastrin-mediated Signaling, Chronic Myeloid Leukemia Signaling, Clathrin-mediated Endocytosis Signaling, CNTF Signaling, Colorectal Cancer Metastasis Signaling, CREB Signaling in Neurons, CTLA4 Signaling in Cytotoxic T Lymphocytes, CXCR4 Signaling, Dendritic Cell Maturation, Docosahexaenoic Acid (DHA) Signaling, EGF Signaling, EIF2 Signaling, Endometrial Cancer Signaling, Endothelin-1 Signaling, eNOS Signaling, Ephrin A Signaling, Ephrin Receptor Signaling, ErbB Signaling, ErbB2-ErbB3 Signaling, ErbB4 Signaling, ERK/MAPK Signaling, Erythropoietin Signaling, Estrogen Receptor Signaling, Estrogen-Dependent Breast Cancer Signaling, FAK Signaling, Fc Epsilon RI Signaling, FcγRIIB Signaling in B Lymphocytes, FGF Signaling, FLT3 Signaling in Hematopoietic Progenitor Cells, fMLP Signaling in Neutrophils, G Beta Gamma Signaling, G-Protein Coupled Receptor Signaling, Gap Junction Signaling, GDNF Family Ligand-Receptor Interactions, Germ Cell-Sertoli Cell Junction Signaling, Glioblastoma Multiforme Signaling, Glioma Invasiveness Signaling, Glioma Signaling, Glucocorticoid Receptor Signaling, GM-CSF Signaling, GNRH Signaling, Growth Hormone Signaling, Gα12/13 Signaling, Gαi Signaling, Gαq Signaling, HER-2 Signaling in Breast Cancer, Hereditary Breast Cancer Signaling, HGF Signaling, HIF1α Signaling, HMGB1 Signaling, Human Embryonic Stem Cell Pluripotency, Huntington's Disease Signaling, iCOS-iCOSL Signaling in T Helper Cells, IGF-1 Signaling, IL-12 Signaling and Production in Macrophages, IL-15 Signaling, IL-17 Signaling, IL-17A Signaling in Airway Cells, IL-2 Signaling, IL-3 Signaling, IL-4 Signaling, IL-6 Signaling, IL-8 Signaling, IL-9 Signaling, ILK Signaling, Insulin Receptor Signaling, Integrin Signaling, JAK/Stat Signaling, Leptin Signaling in Obesity, Leukocyte Extravasation Signaling, LPS-stimulated MAPK Signaling, Lymphotoxin β Receptor Signaling, Macropinocytosis Signaling, Melanocyte Development and Pigmentation Signaling, Melanoma Signaling, Molecular Mechanisms of Cancer, Mouse Embryonic Stem Cell Pluripotency, MSP-RON Signaling Pathway, mTOR Signaling, Myc Mediated Apoptosis Signaling, Natural Killer Cell Signaling, Neuregulin Signaling, Neuropathic Pain Signaling In Dorsal Horn Neurons, Neurotrophin/TRK Signaling, NF-κB Activation by Viruses, NF-κB Signaling, NGF Signaling, Nitric Oxide Signaling in the Cardiovascular System, Non-Small Cell Lung Cancer Signaling, NRF2-mediated Oxidative Stress Response, Oncostatin M Signaling, Ovarian Cancer Signaling, P2Y Purigenic Receptor Signaling Pathway, p53 Signaling, p70S6K Signaling, PAK Signaling, Pancreatic Adenocarcinoma Signaling, Paxillin Signaling, PDGF Signaling, PEDF Signaling, phagosome formation, Phospholipase C Signaling, PI3K/AKT Signaling, PKCθ Signaling in T Lymphocytes, PPAR Signaling, PPARα/RXRα Activation, Production of Nitric Oxide and Reactive Oxygen Species in Macrophages, Prolactin Signaling, Prostate Cancer Signaling, PTEN Signaling, Rac Signaling, RANK Signaling in Osteoclasts, Reelin Signaling in Neurons, Regulation of Cellular Mechanics by Calpain Protease, Regulation of eIF4 and p70S6K Signaling, Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes, Regulation of the Epithelial-Mesenchymal Transition Pathway, Relaxin Signaling, Renal Cell Carcinoma Signaling, Renin-Angiotensin Signaling, Role of IL-17A in Arthritis, Role of JAK1 and JAK3 in γc Cytokine Signaling, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis, Role of NANOG in Mammalian Embryonic Stem Cell Pluripotency, Role of NFAT in Cardiac Hypertrophy, Role of NFAT in Regulation of the Immune Response, Role of Osteoblasts, Osteoclasts and Chondrocytes in Rheumatoid Arthritis, Role of p14/p19ARF in Tumor Suppression, Role of Pattern Recognition Receptors in Recognition of Bacteria and Viruses, Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, Role of Tissue Factor in Cancer, SAPK/JNK Signaling, Signaling by Rho Family GTPases, Small Cell Lung Cancer Signaling, Sphingosine-1-phosphate Signaling, Superpathway of Inositol Phosphate Compounds, Systemic Lupus Erythematosus Signaling, T Cell Receptor Signaling, Tec Kinase Signaling, Telomerase Signaling, TGF-β Signaling, Thrombin Signaling, Thrombopoietin Signaling, TR/RXR Activation, TREM1 Signaling, Type II Diabetes Mellitus Signaling, UVA-Induced MAPK Signaling, UVB-Induced MAPK Signaling, VEGF Family Ligand-Receptor Interactions, VEGF Signaling, Virus Entry via Endocytic Pathways, Xenobiotic Metabolism Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) IGF2BP3 0.041 -1.850  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) IRF9 0.018 -2.200 Activation of IRF by Cytosolic Pattern Recognition Receptors, Interferon Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) KIF1B 0.000 -1.790  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) LASP1 0.000 -5.070 IL-8 Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) MAP2K2 0.000 -1.590 14-3-3-mediated Signaling, 4-1BB Signaling in T Lymphocytes, Actin Cytoskeleton Signaling, Acute Myeloid Leukemia Signaling, Acute Phase Response Signaling, Aldosterone Signaling in Epithelial Cells, Antiproliferative Role of Somatostatin Receptor 2, Apoptosis Signaling, Axonal Guidance Signaling, B Cell Receptor Signaling, Bladder Cancer Signaling, BMP signaling pathway, Breast Cancer Regulation by Stathmin1, cAMP-mediated signaling, Cancer Drug Resistance By Drug Efflux, Cardiac Hypertrophy Signaling, CCR3 Signaling in Eosinophils, CD27 Signaling in Lymphocytes, CD28 Signaling in T Helper Cells, CD40 Signaling, CDK5 Signaling, Chemokine Signaling, Cholecystokinin/Gastrin-mediated Signaling, Chronic Myeloid Leukemia Signaling, CNTF Signaling, Colorectal Cancer Metastasis Signaling, Corticotropin Releasing Hormone Signaling, CREB Signaling in Neurons, CXCR4 Signaling, EIF2 Signaling, Endometrial Cancer Signaling, Ephrin Receptor Signaling, ErbB Signaling, ErbB2-ErbB3 Signaling, ErbB4 Signaling, ERK/MAPK Signaling, Erythropoietin Signaling, Estrogen Receptor Signaling, FAK Signaling, Fc Epsilon RI Signaling, FLT3 Signaling in Hematopoietic Progenitor Cells, fMLP Signaling in Neutrophils, G-Protein Coupled Receptor Signaling, Gap Junction Signaling, GDNF Family Ligand-Receptor Interactions, Germ Cell-Sertoli Cell Junction Signaling, Glioblastoma Multiforme Signaling, Glioma Signaling, Glucocorticoid Receptor Signaling, GM-CSF Signaling, GNRH Signaling, Gα12/13 Signaling, Gαq Signaling, Gαs Signaling, HGF Signaling, HMGB1 Signaling, IGF-1 Signaling, IL-12 Signaling and Production in Macrophages, IL-15 Signaling, IL-17 Signaling, IL-17A Signaling in Airway Cells, IL-2 Signaling, IL-3 Signaling, IL-6 Signaling, IL-8 Signaling, Insulin Receptor Signaling, Integrin Signaling, JAK/Stat Signaling, Leptin Signaling in Obesity, Leukocyte Extravasation Signaling, LPS-stimulated MAPK Signaling, Melanocyte Development and Pigmentation Signaling, Melanoma Signaling, Melatonin Signaling, Molecular Mechanisms of Cancer, Mouse Embryonic Stem Cell Pluripotency, Natural Killer Cell Signaling, Neuregulin Signaling, Neurotrophin/TRK Signaling, NGF Signaling, Nitric Oxide Signaling in the Cardiovascular System, Non-Small Cell Lung Cancer Signaling, NRF2-mediated Oxidative Stress Response, Oncostatin M Signaling, Ovarian Cancer Signaling, P2Y Purigenic Receptor Signaling Pathway, p70S6K Signaling, PAK Signaling, Pancreatic Adenocarcinoma Signaling, PDGF Signaling, Phospholipase C Signaling, PI3K Signaling in B Lymphocytes, PI3K/AKT Signaling, PPAR Signaling, PPARα/RXRα Activation, Prolactin Signaling, Prostate Cancer Signaling, Protein Kinase A Signaling, PTEN Signaling, Pyridoxal 5'-phosphate Salvage Pathway, Rac Signaling, RANK Signaling in Osteoclasts, Regulation of eIF4 and p70S6K Signaling, Regulation of IL-2 Expression in Activated and Anergic T Lymphocytes, Regulation of the Epithelial-Mesenchymal Transition Pathway, Renal Cell Carcinoma Signaling, Renin-Angiotensin Signaling, Role of IL-17A in Arthritis, Role of IL-17F in Allergic Inflammatory Airway Diseases, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis, Role of MAPK Signaling in the Pathogenesis of Influenza, Role of NANOG in Mammalian Embryonic Stem Cell Pluripotency, Role of NFAT in Cardiac Hypertrophy, Role of NFAT in Regulation of the Immune Response, Role of PI3K/AKT Signaling in the Pathogenesis of Influenza, Salvage Pathways of Pyrimidine Ribonucleotides, Sertoli Cell-Sertoli Cell Junction Signaling, Signaling by Rho Family GTPases, STAT3 Pathway, Synaptic Long Term Depression, Synaptic Long Term Potentiation, T Cell Receptor Signaling, Telomerase Signaling, TGF-β Signaling, Thrombin Signaling, Thrombopoietin Signaling, Thyroid Cancer Signaling, UVC-Induced MAPK Signaling, VEGF Family Ligand-Receptor Interactions, VEGF Signaling, Xenobiotic Metabolism Signaling, α-Adrenergic Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) MAPKAPK2 0.000 -2.530 Cardiac Hypertrophy Signaling, CD40 Signaling, FGF Signaling, IL-17 Signaling, IL-6 Signaling, p38 MAPK Signaling, RAR Activation, Role of IL-17A in Arthritis, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) MICU1 0.009 -2.080 Calcium Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) MPRIP 0.000 -1.630 Actin Cytoskeleton Signaling, CCR3 Signaling in Eosinophils, Cdc42 Signaling, Cellular Effects of Sildenafil (Viagra), Chemokine Signaling, Integrin Signaling, Phospholipase C Signaling, Regulation of Actin-based Motility by Rho, RhoA Signaling, Thrombin Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human High (predicted) MTPN 0.010 -4.220  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) NAP1L1 0.000 -5.190  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) NPRL3 0.001 -2.140  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) PLEK 0.000 -3.490  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) PPP1R18 0.033 -4.160  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) PSAP 0.000 -1.860 Lipid Antigen Presentation by CD1
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) RAB11FIP3 0.000 -7.870  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) SECISBP2 0.000 -2.500  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) SH3BGRL2 0.000 -12.590  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) SLC35E1 0.000 -3.270  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) SLC9A1 0.006 -4.300 Actin Cytoskeleton Signaling, Aldosterone Signaling in Epithelial Cells, Signaling by Rho Family GTPases
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) TGOLN2 0.000 -2.570  
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) TJP2 0.005 -2.120 Hepatic Cholestasis, HIPPO signaling, Sertoli Cell-Sertoli Cell Junction Signaling, Tight Junction Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) TWSG1 0.000 -2.450 Antiproliferative Role of TOB in T Cell Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) UCP2 0.049 -4.070 Mitochondrial Dysfunction, TR/RXR Activation
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) ULK1 0.000 -4.635 AMPK Signaling, autophagy, mTOR Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human Moderate (predicted) VAMP3 0.000 -1.780 Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes, Huntington's Disease Signaling, phagosome maturation, Tight Junction Signaling
hsa-miR-1226 0.011 1.800 TargetScan Human High (predicted) VASH1 0.007 -1.690  
hsa-miR-1231 0.003 24.400 TargetScan Human High (predicted) AZIN1 0.015 -4.670 Polyamine Regulation in Colon Cancer
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) BTG1 0.000 -1.990 Cell Cycle Regulation by BTG Family Proteins
hsa-miR-1231 0.003 24.400 TargetScan Human High (predicted), Moderate (predicted) BTN3A2 0.003 -2.840  
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) CABLES1 0.000 -1.940 CDK5 Signaling
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) CARD8 0.000 -1.640  
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) CTDSPL 0.000 -16.420  
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) DNAJC9 0.000 -2.180 Aldosterone Signaling in Epithelial Cells, NRF2-mediated Oxidative Stress Response, Protein Ubiquitination Pathway
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) EGF 0.000 -2.220 Actin Cytoskeleton Signaling, Axonal Guidance Signaling, Bladder Cancer Signaling, Caveolar-mediated Endocytosis Signaling, Clathrin-mediated Endocytosis Signaling, Colorectal Cancer Metastasis Signaling, EGF Signaling, Ephrin Receptor Signaling, Epithelial Adherens Junction Signaling, ErbB Signaling, ERK5 Signaling, FAK Signaling, Gap Junction Signaling, Glioblastoma Multiforme Signaling, Glioma Signaling, GNRH Signaling, Hepatic Fibrosis / Hepatic Stellate Cell Activation, HER-2 Signaling in Breast Cancer, Huntington's Disease Signaling, IL-8 Signaling, Macropinocytosis Signaling, Neuregulin Signaling, NF-κB Signaling, Non-Small Cell Lung Cancer Signaling, Ovarian Cancer Signaling, Pancreatic Adenocarcinoma Signaling, Regulation of Cellular Mechanics by Calpain Protease, Regulation of the Epithelial-Mesenchymal Transition Pathway, Telomerase Signaling, Thrombin Signaling
hsa-miR-1231 0.003 24.400 TargetScan Human High (predicted) GLG1 0.000 -1.790 Agranulocyte Adhesion and Diapedesis, Atherosclerosis Signaling, Granulocyte Adhesion and Diapedesis
hsa-miR-1231 0.003 24.400 TargetScan Human High (predicted) HECTD4 0.000 -2.070  
hsa-miR-1231 0.003 24.400 TargetScan Human High (predicted) KIAA0513 0.000 -7.100  
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) MAPKAPK2 0.000 -2.530 Cardiac Hypertrophy Signaling, CD40 Signaling, FGF Signaling, IL-17 Signaling, IL-6 Signaling, p38 MAPK Signaling, RAR Activation, Role of IL-17A in Arthritis, Role of Macrophages, Fibroblasts and Endothelial Cells in Rheumatoid Arthritis
hsa-miR-1231 0.003 24.400 TargetScan Human Moderate (predicted) MBP 0.000 -12.630  
hsa-miR-1231 0.003 24.400

DISCUSSION

Since mRNAs are subjected to regulation by miRNAs, it is important to assess the changes both in mRNA and miRNA expression levels of platelets during storage. The functional analysis of potential miRNA targets showing inverse correlation with mRNA expression identified several signaling pathways. The actin mediated cytoskeleton signaling and integrin signaling were the top most signaling pathways implicated in platelet functions such as aggregation, granule secretion and activation. Flaumenhaft et al., [9] also reported regulatory effect of act in cytoskeleton signaling on platelet granule secretion. In a previous study, 12 members of integrin signaling pathway were identified as contributor of storage lesion development [10]. Other significant pathways implicated in platelets during storage were focal adhesion pathways, IGF-1 signaling pathway and ephrin receptor signaling pathway. Integrin and focal adhesion pathways have been reported to be involved in early storage lesion in apheresis platelets [11]. IGF-1 signaling pathway has been reported to regulate platelet activation [12-13] and the ephrin receptor signaling pathway has been reported to regulate platelet granule secretion, Rap1 activation, platelet adhesion and aggregation [14-16].

The morphology of platelets do change during storage and platelet movement following transfusion into patients is critical as platelets are supposed to migrate rapidly to the site of damage to initiate formation of “platelet plug” to seal the damaged blood vessel and subsequent wound healing [17,18]. The change in expression levels of different genes identified in our study is able to reflect the changes in platelets morphology and physiological functions during storage. Since these molecular changes in terms of their ability to activate, aggregate and adhere as well as interact with each other are representative of the quality of platelets in storage, the differences in the expression levels of these genes may help develop platelet storage quality biomarkers predictive of their performance in platelet-transfused patients.

Apoptosis is an important process implicated in platelet storage lesion [19-20]. Our IPA analysis found a list of 27 apoptosis related genes. The list included genes such as CASP3 and BCL2L1 which are important players of apoptosis [21-23]. These candidate genes and the miRNAs that target these genes could be important in assessing the platelet quality during storage. The treatment of platelet concentrate with caspase inhibitor has been shown to increase the survival of the platelets [21]. Similar results were reported with use of antibodies against caspases [24]. The existence of apoptotic machinery in platelets and its alteration during storage provides another alternative for intervention to improve the quality of platelets during storage. The miRNAs targeting the genes of these apoptotic molecules could also serve as potential quality biomarkers of stored platelets.

In conclusion, the results reported here clearly identify the potential of miRNAs in regulating functions relevant to the platelet storage lesions. our analyses of the data we generated demonstrates that in fact there are several platelet signaling and functional pathways that are potentially subject to miRNA:mRNA interactions and 7 miRNAs that we identified to be upregulated (miR-320b, miR-1-3p, miR-214-3p, miR-197-3p, miR-129-5p, miR-183-5p and miR-292b-5p) could serve as potential platelets storage biomarkers. There is very limited information on functional role miRNAs in platelets. Of the seven miRNAs identified in our study only miR-320b has been studied in relation to its specific function in platelets. Activated platelets have been reported to release miR-320b in circulation where it has been found to regulate expression of Intercellular Adhesion Molecule-1 (ICAM-1) in endothelial cell [25]. Further experimental studies are required to assess the role of these miRNA:mRNA pairs.

ACKNOWLEDGEMENT

ND was a recipient of a postdoctoral fellowship at the Center for Biologics Evaluation and Research (CBER) administered by the Oak Ridge Institute for Science and Education (ORISE) through an intra-agency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration.

AUTHORSHIP CONTRIBUTIONS

ND designed the study, performed experiments, analyzed data and wrote manuscript. CDA provided training to ND and also participated in designing the study and writing the manuscript. SK assisted ND in obtaining samples from NIH Blood Bank and ordering laboratory supplies and reagents needed for all experiments.

DISCLOSURE OF CONFLICTS OF INTEREST

The authors declare that they have no conflicts of interest.

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SUPPLEMENTARY TABLE 1

Symbol Fold Change (Day 5 vs. Day 0) Symbol Fold Change (Day 9 vs. Day 0)
ACTRT1 2.3 COL8A2 2.9
COL8A2 2.2 AKAP7 2.9
CSNK2A1 2.2 LOC645932 2.9
LOC100130769 2.2 USP33 2.8
OR2A42 1.9 RN7SK 2.8
FKBP3 1.8 LOC645931 2.7
ROCK1 1.8 MYL12A 2.7
FNIP2 1.7 CSNK2A1 2.7
YIPF1 1.7 SIPA1L3 2.5
IL7 1.7 ACTRT1 2.5
LOC100133939 1.7 C9orf62 2.5
MAK10 1.7 FZD7 2.4
SLC25A45 1.6 LOC100130769 2.4
DNA2 1.6 TTK 2.4
MED31 1.6 IL7 2.4
LCLAT1 1.6 OR2A42 2.4
IGSF11 1.6 LOC100133747 2.4
LYPD3 1.6 SNORD13 2.3
TERF1 1.6 LCLAT1 2.3
FAM13A 1.6 ROCK1 2.3
TTK 1.6 RNASEH2B 2.3
LOC644632 1.6 SDCCAG1 2.3
LOC646548 1.6 LARP1B 2.2
TRIO 1.6 FBXO2 2.2
DLEU1 1.5 DNHD2 2.1
LRRCC1 1.5 FKBP3 2.1
CISD2 1.5 LARP7 2.0
TMEM55A 1.5 ITGA7 2.0
MGC3196 1.5 FGF18 2.0
PRKACB 1.5 MAK10 2.0
ZSWIM4 1.5 YIPF1 2.0
HGD 1.5 PTMS 2.0
LOC100129195 1.5 ZSWIM4 2.0
LOC100132918 1.5 LOC402538 2.0
POLR2J2 1.5 RASA4P 2.0
LOC641814 -1.5 PTPN7 1.9
CIRBP -1.5 ATP5I 1.9
LOC100133551 -1.5 C12orf24 1.9
ARPC4 -1.6 C11orf10 1.9
CIB1 -1.6 COX7B 1.9
LOC284821 -1.6 FLJ44054 1.9
RPL14L -1.6 CCDC53 1.9
UBE2M -1.6 RRM1 1.9
LOC100129553 -1.6 LOC644914 1.9
UIMC1 -1.6 KIAA1967 1.9
LOC390345 -1.7 LOC729776 1.8
LOC650152 -1.8 SNHG9 1.8
PSAP -1.9 LRRCC1 1.8
LOC100130477 -2.0 DUSP15 1.8
LOC441013 -2.0 THOC2 1.8
NFE2 -2.0 FEZ1 1.7
ODC1 -2.0 PSMA6 1.7
LOC440589 -2.2 SNORD3A 1.7
DIMT1L -3.4 C1orf50 1.7
    GNG8 1.7
    FXYD1 1.7
    LOC100133477 1.7
    ATP5L 1.6
    NOP10 1.6
    DLEU1 1.6
    NDUFA3 1.5
    LOC729009 1.5
    ZFAND1 1.5
    EIF1AY 1.5
    LSM1 1.5
    CIC -1.5
    CLEC2L -1.5
    DYRK1A -1.5
    HIST1H2BD -1.5
    MYO1C -1.5
    PLOD1 -1.5
    RHD -1.5
    TTC15 -1.5
    UQCRH -1.5
    DNAJA2 -1.5
    TMSB10 -1.5
    C17orf90 -1.5
    C5orf15 -1.5
    DSTN -1.5
    GTF3C5 -1.5
    LOC728139 -1.5
    SEC16A -1.5
    ARID3B -1.5
    ATP2A2 -1.5
    C9orf78 -1.5
    CDV3 -1.5
    LOC390466 -1.5
    LOC730990 -1.5
    NEURL1B -1.5
    PAFAH1B1 -1.5
    PPP2CB -1.5
    SCFD2 -1.5
    SLCO3A1 -1.5
    AP1M2 -1.5
    ARHGAP1 -1.5
    COPE -1.5
    DDX41 -1.5
    FAM100B -1.5
    FAM13B -1.5
    IRS1 -1.5
    LOC647340 -1.5
    POL3S -1.5
    SELT -1.5
    UPF1 -1.5
    AKAP13 -1.5
    BEST2 -1.5
    DNAH2 -1.5
    ITFG1 -1.5
    LOC100133649 -1.5
    LPIN2 -1.5
    MAP2K1 -1.5
    MAPK8IP3 -1.5
    MTHFD2 -1.5
    PARK7 -1.5
    RBM4 -1.5
    CNPY3 -1.5
    KLHDC3 -1.5
    LOC728368 -1.5
    NCOA6 -1.5
    PAPSS2 -1.5
    PLOD2 -1.5
    RNF10 -1.5
    SHCBP1 -1.5
    SRPR -1.5
    AHCTF1 -1.5
    AP3M2 -1.5
    KLF13 -1.5
    RNF44 -1.5
    BCL7B -1.5
    C19orf31 -1.5
    CS -1.5
    FNBP1 -1.5
    LGALS8 -1.5
    LOC649679 -1.5
    MTCH1 -1.5
    NCOA3 -1.5
    N-PAC -1.5
    PDLIM1 -1.5
    PRRT3 -1.5
    RAF1 -1.5
    RNF14 -1.5
    SAPS3 -1.5
    SHKBP1 -1.5
    STK40 -1.5
    UBQLN3 -1.5
    ARID1A -1.5
    DENND3 -1.5
    LOC100132394 -1.5
    LOC100132593 -1.5
    LOC203547 -1.5
    LOC339970 -1.5
    MID1IP1 -1.5
    ORAI3 -1.5
    TXNDC12 -1.5
    UBB -1.5
    ANXA2P2 -1.6
    LOC552889 -1.6
    MAP2K3 -1.6
    NAG18 -1.6
    SCYL1 -1.6
    TTC7B -1.6
    XPO6 -1.6
    ATF4 -1.6
    ATP5A1 -1.6
    C15orf39 -1.6
    C20orf11 -1.6
    CCR6 -1.6
    CUGBP2 -1.6
    RGS10 -1.6
    TMEM183B -1.6
    TNIP1 -1.6
    ETS1 -1.6
    GTDC1 -1.6
    KBTBD2 -1.6
    VIL2 -1.6
    ZMIZ2 -1.6
    MTMR14 -1.6
    RGS6 -1.6
    TBC1D14 -1.6
    YY1 -1.6
    LOC100133465 -1.6
    MAP2K2 -1.6
    SYT11 -1.6
    TRIP12 -1.6
    BCL2L1 -1.6
    COBRA1 -1.6
    ELMO2 -1.6
    GABARAPL2 -1.6
    ITIH5 -1.6
    LOC400446 -1.6
    LOC401052 -1.6
    LOC646723 -1.6
    LOC728553 -1.6
    CCNJL -1.6
    ORC6L -1.6
    PANK2 -1.6
    UHRF1BP1 -1.6
    ARAP1 -1.6
    LOC643738 -1.6
    LOC648210 -1.6
    MRPL18 -1.6
    PUM2 -1.6
    SPG3A -1.6
    TMEM183A -1.6
    VTI1B -1.6
    DIABLO -1.6
    GATA2 -1.6
    LOC649049 -1.6
    MPRIP -1.6
    SCAND1 -1.6
    SERF2 -1.6
    TBC1D20 -1.6
    C16orf7 -1.6
    CARD8 -1.6
    CASP6 -1.6
    IP6K1 -1.6
    CHFR -1.7
    CORO1A -1.7
    NCOR2 -1.7
    ARHGEF3 -1.7
    LOC650029 -1.7
    NECAP2 -1.7
    PCSK7 -1.7
    RP11-529I10.4 -1.7
    TMEM189 -1.7
    VIL1 -1.7
    YWHAB -1.7
    LOC650034 -1.7
    MSRA -1.7
    VASP -1.7
    ZC3H7A -1.7
    HLA-DRA -1.7
    SNRPB -1.7
    CHST12 -1.7
    LOC644739 -1.7
    NLRX1 -1.7
    PSMF1 -1.7
    VASH1 -1.7
    CHMP4B -1.7
    FBXW11 -1.7
    FOXO1 -1.7
    LOC728787 -1.7
    SRGN -1.7
    WIPI2 -1.7
    CABC1 -1.7
    CHSY1 -1.7
    COASY -1.7
    N4BP2L1 -1.7
    SH3KBP1 -1.7
    SPIRE1 -1.7
    ARHGDIA -1.7
    CBL -1.7
    DULLARD -1.7
    EIF3G -1.7
    EZR -1.7
    HCLS1 -1.7
    LOC399942 -1.7
    SMG7 -1.7
    MLEC -1.7
    CD44 -1.8
    FADD -1.8
    FASTKD5 -1.8
    INPP5A -1.8
    QSOX1 -1.8
    C6orf106 -1.8
    LTB -1.8
    MTHFR -1.8
    RBM14 -1.8
    SFRS9 -1.8
    SNX6 -1.8
    WNK1 -1.8
    SRF -1.8
    UBE2G1 -1.8
    HYAL3 -1.8
    NR1H2 -1.8
    VAMP3 -1.8
    ATG9A -1.8
    B4GALT1 -1.8
    GLG1 -1.8
    KIF1B -1.8
    YPEL2 -1.8
    ZFP91 -1.8
    ANKRD10 -1.8
    C16orf63 -1.8
    RAP2A -1.8
    SEPX1 -1.8
    SYF2 -1.8
    TMEM50A -1.8
    FGR -1.8
    BRD2 -1.8
    IVNS1ABP -1.8
    LOC148430 -1.8
    CHMP1B -1.8
    PRTFDC1 -1.8
    CMTM2 -1.8
    GUCY1B3 -1.8
    MTHFD2L -1.8
    SMCR7L -1.8
    VPS26B -1.8
    IGF2BP3 -1.9
    ITGA2 -1.9
    NUMB -1.9
    REPS2 -1.9
    ARMC7 -1.9
    CAV2 -1.9
    CLDN15 -1.9
    AKT1 -1.9
    PPP4C -1.9
    PTP4A3 -1.9
    RPRC1 -1.9
    TTC39B -1.9
    LOC493754 -1.9
    GP6 -1.9
    INPPL1 -1.9
    LOC441455 -1.9
    UBE2M -1.9
    ANKRD28 -1.9
    C17orf62 -1.9
    CDS2 -1.9
    EPOR -1.9
    PDGFC -1.9
    RALBP1 -1.9
    SLA2 -1.9
    C14orf147 -1.9
    OXTR -1.9
    PHTF1 -1.9
    SLC2A8 -1.9
    XPO7 -1.9
    KLHL6 -1.9
    LRMP -1.9
    WDR40A -1.9
    VIM -1.9
    ATP5D -1.9
    CABLES1 -1.9
    CHMP1A -1.9
    VISA -1.9
    ANTXR2 -2.0
    CLEC16A -2.0
    MPST -2.0
    RCOR3 -2.0
    SNAP29 -2.0
    TMEM14C -2.0
    POLR2A -2.0
    BNIP3L -2.0
    C6orf85 -2.0
    CDKL1 -2.0
    CEBPB -2.0
    LOC645173 -2.0
    NHP2L1 -2.0
    MFSD6 -2.0
    SLC35D3 -2.0
    BTG1 -2.0
    CTNNBIP1 -2.0
    HERC1 -2.0
    KATNB1 -2.0
    LOC441506 -2.0
    NKG7 -2.0
    PAM -2.0
    11-Sep -2.0
    FAM108A3 -2.0
    HIST1H3F -2.0
    PPM1G -2.0
    TCF25 -2.0
    FNBP1L -2.0
    SSBP2 -2.0
    EEF1G -2.0
    EHBP1 -2.0
    LOC642755 -2.0
    LOC648249 -2.0
    PTGIR -2.0
    VPS37C -2.0
    ACSS2 -2.0
    CYFIP1 -2.0
    DLG4 -2.0
    KIAA1545 -2.0
    KIF3C -2.0
    WWC3 -2.0
    DDA1 -2.0
    PACSIN2 -2.0
    UBE1 -2.0
    ZNF364 -2.0
    C7orf49 -2.1
    CD36 -2.1
    XRCC6 -2.1
    C12orf51 -2.1
    DSCR3 -2.1
    LOC440927 -2.1
    NCK2 -2.1
    ABHD4 -2.1
    CBARA1 -2.1
    LOC390345 -2.1
    NCOA7 -2.1
    P2RY12 -2.1
    STRN4 -2.1
    TGFBR2 -2.1
    UBAC1 -2.1
    CTBP1 -2.1
    PCTP -2.1
    SVIL -2.1
    GTF2IP1 -2.1
    ATP6V1B2 -2.1
    CD47 -2.1
    CLPTM1L -2.1
    MCM7 -2.1
    PKP4 -2.1
    TJP2 -2.1
    ACTN4 -2.1
    TMEM63A -2.1
    VPS8 -2.1
    ENKUR -2.1
    C16orf35 -2.1
    CLTA -2.1
    EIF4E3 -2.1
    EIF4H -2.1
    LTA -2.1
    NKIRAS2 -2.1
    RPL13A -2.1
    VHL -2.1
    DNAJC8 -2.2
    HIST1H3H -2.2
    LOC401537 -2.2
    PRPF8 -2.2
    RASA3 -2.2
    SLC25A3 -2.2
    CD37 -2.2
    LOC644330 -2.2
    ARHGEF12 -2.2
    KIAA0427 -2.2
    LOC728069 -2.2
    RNF38 -2.2
    SET -2.2
    TM2D2 -2.2
    PBX3 -2.2
    RICS -2.2
    RPLP0 -2.2
    SORT1 -2.2
    TXNRD1 -2.2
    ADRBK1 -2.2
    ARHGEF18 -2.2
    DNAJC9 -2.2
    ECGF1 -2.2
    ERICH1 -2.2
    TSC22D4 -2.2
    IRF9 -2.2
    PFDN6 -2.2
    PSMD2 -2.2
    RILPL2 -2.2
    EGF -2.2
    ZC3H11B -2.2
    C10orf26 -2.3
    HNRPUL1 -2.3
    PRKCA -2.3
    ATP6V0B -2.3
    MEF2D -2.3
    POLR1D -2.3
    CLCN7 -2.3
    PGK1 -2.3
    NIN -2.3
    LOC286444 -2.3
    MGEA5 -2.3
    RPS2 -2.3
    TMEM60 -2.3
    TUBB1 -2.3
    SLBP -2.3
    KIFAP3 -2.3
    PRKCQ -2.3
    PTPN6 -2.3
    PPP1CA -2.3
    HERC6 -2.3
    ARL8B -2.3
    ISCA1 -2.3
    LAMC1 -2.3
    RALB -2.3
    GFOD1 -2.3
    KIAA1147 -2.3
    MAN2A2 -2.3
    TBC1D13 -2.3
    MRFAP1 -2.3
    RPS6KB2 -2.3
    FLOT2 -2.4
    TERF2IP -2.4
    UBE2D3 -2.4
    FAM65B -2.4
    LOC388654 -2.4
    P4HB -2.4
    ATP6V0A1 -2.4
    ELMO1 -2.4
    SSH1 -2.4
    CMTM3 -2.4
    ETV6 -2.4
    FLI1 -2.4
    JUND -2.4
    NBEAL2 -2.4
    BCR -2.4
    GNA12 -2.4
    LOC100130291 -2.4
    LOC387867 -2.4
    RAB6B -2.4
    LOC728661 -2.4
    AP1B1 -2.4
    TXNIP -2.4
    C5orf21 -2.4
    CLIC1 -2.4
    FAM120A -2.4
    HDAC1 -2.4
    SYNM -2.4
    TXNL4B -2.4
    VCP -2.4
    LOC286157 -2.4
    ACADVL -2.4
    C16orf30 -2.4
    LOC642031 -2.4
    TWSG1 -2.5
    LOC100133591 -2.5
    SHC1 -2.5
   

Citation: Dahiya N, Kulkarni S, Atreya CD (2016) Ingenuity Pathway Analysis of miRNAs and mRNAs in Stored Platelets Identifies the Potential of miRNAs in Regulating Functions Relevant to Storage Lesions. J Hematol Blood Transfus Disord 3: 012.

Copyright: © 2016  Chintamani D Atreya, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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