Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field
Abstract
:1. Introduction
2. Results
2.1. Identification of DEGs
2.2. Functional and Pathway Enrichment Analysis of Identified Modules Associated with DEGs
2.3. Module Screening from the PPI Network
2.4. Sub-Localization Expression Analysis of Hub Genes
2.5. Mining Genetic Alterations Connected with Hub Genes by cBioportal
2.6. The Eight Hub Genes Expressed in Leukemia by Using Oncomine
2.7. Protein Modeling
2.8. Molecular Dynamics and Simulation
3. Discussion
3.1. Electric Field: Jurkat Cells
3.2. Electric Field: Jurkat Cell Signal Pathway Change
3.3. Electric Field: Hub Gene Analysis
3.4. Electric Field: Jurkat Cell Gene Expression Change
3.5. Electric Field: The Effects of nsPEF on Cancer Cells
3.6. The Limitations of This Study
4. Materials and Methods
4.1. Main Steps
4.2. Microarray Data
4.3. Identification of DEGs
4.4. Functional Enrichment Analysis for DEGs
4.5. Protein–Protein Interaction (PPI) Network Construction and Module Analysis
4.6. Exploring Sub-Localization Expression of Hub Genes by Human Protein Atlas
4.7. Exploring Jurkat Genomics Data by cBio Cancer Genomics Portal
4.8. The Hub Genes Analysis by Using the Oncomine Database
4.9. Protein Modeling
4.10. De Novo Modeling of Proteins
4.11. Molecular Dynamics Simulations
4.11.1. Molecular Dynamic Simulation: Protein in Water
4.11.2. Molecular Dynamic Simulation: Protein under nsPEFs
4.11.3. Molecular Dynamic Simulation Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
BP | biological process |
BRD4/MYC | bromodomain-containing protein 4/MYC proto-oncogene |
cBioPortal | cBio Cancer Genomics Portal |
CC | cell component |
DEGs | differentially expressed genes |
FC | fold control |
GO | gene ontology |
IL7R | interleukin-7 receptor |
KEGG | Kyoto Encyclopedia of Genes and Genomes pathway |
MCODE | molecular complex detection |
MF | molecular function |
NOTCH1 | notch receptor 1 |
nsPEF | nanosecond pulsed electric field |
PPI | protein–protein interaction |
PTEN | phosphatase and tensin homolog |
RMSD | molecular dynamic analysis including root mean square deviation |
RMSF | root mean square fluctuation |
SINE | selective inhibitor of nuclear export |
nsPEF | nanosecond pulsed electric field |
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Pathway Type (Up-Regulated) | Up-Regulation (Group 1) | Up-Regulation (Group 2) | Pathway Type (Down-Regulated) | Down-Regulation (Group 1) | Down-Regulation (Group 2) |
---|---|---|---|---|---|
General (biological process—BP) | negative regulation of cell proliferation | negative regulation of cell proliferation | General (BP) | metabolism of RNA | metabolism of RNA |
Specific (BP) | PID NFAT TF pathway | PID NFAT TF pathway | General (BP) | cell cycle | cell cycle |
General (molecular function—MF) | regulation of double-strand break repair via homologous recombination | regulation of double-strand break repair via homologous recombination | General (MF) | ncRNA metabolic process | ncRNA metabolic process |
General (MF) | negative regulation of phosphate metabolic process | negative regulation of phosphate metabolic process | General (BP) | DNA repair | DNA repair |
General (BP) | chromatin remodeling | chromatin remodeling | General (BP) | nuclear export | nuclear export |
General (MF) | maintenance of cell number | maintenance of cell number | General (MF) | cell cycle phase transition | cell cycle phase transition |
Specific (BP) | O-glycan processing | T cell mediated cytotoxicity | General (MF) | regulation of chromosome organization | regulation of chromosome organization |
General (BP) | mRNA processing | regulation of blood pressure | General (MF) | tRNA metabolic process | tRNA metabolic process |
Specific (BP) | regulation of PTEN gene transcription | histone modification | General (BP) | mitotic sister chromatid segregation | mitotic sister chromatid segregation |
General (MF) | glucose homeostasis | dephosphorylation | General (BP) | DNA replication | DNA replication |
General (MF) | immune response-regulating cell surface receptor signaling pathway | transcription elongation from RNA polymerase II promoter | General (cellular component—CC) | microtubule cytoskeleton organization | microtubule cytoskeleton organization |
negative regulation of cell cycle | General (BP) | covalent chromatin modification | covalent chromatin modification | ||
General (BP) | organelle biogenesis and maintenance | organelle biogenesis and maintenance | |||
General (MF) | DNA-templated transcription, termination | DNA-templated transcription, termination | |||
General (CC) | macromolecule methylation | macromolecule methylation | |||
General (BP) | organelle localization | organelle localization | |||
General (BP) | ribonucleoprotein complex biogenesis | ribonucleoprotein complex biogenesis | |||
General (BP) | cell cycle | cell cycle | |||
General (BP) | regulation of DNA metabolic process | regulation of DNA metabolic process | |||
General (BP) | DNA geometric change | regulation of cellular response to stress |
Groups | Expression | Pathway ID | Name | Gene Count | % | Genes |
---|---|---|---|---|---|---|
Group 1 | Down-regulated | hsa01100 | Metabolic pathways | 117 | 9.04 | NAMPT, INMT, CHKA, GPAT4, CTPS1, DGKA, DLAT, DLD, DNMT1, EPRS, ALAS1, EXT1, ACSL3, FASN, FECH, SEPHS2, AKR1B1, GANAB, ACSL6, MLYCD, ETHE1, SHPK, PISD, KDSR, GART, GCNT1, GLDC, GLO1, GMDS, GOT2, GPI, PIGW, RIMKLA, GSTM3, HADHA, HK1, HMGCR, IDI1, INPP4A, ACADVL, STT3A, LSS, LTA4H, MAN2A2, MDH2, MGAT5, MPI, ASNS, NDUFA10, ATIC, NDUFB4, NDUFS1, OAT, ODC1, ACO2, OXCT1, PCCA, SEPSECS, PDE8A, INPP5K, PFKP, PGM1, ATP6V1B2, PIK3CD, PI4KA, PI4KB, PLCG1, PLCG2, PGM2, PPT1, ETNK1, SMPD4, CNDP2, AGK, CMAS, INPP5E, AGPAT4, QARS, BCAT1, RPN1, RPN2, SCD, GALNT11, RBKS, SGSH, SHMT1, SORD, TK2, UCK2, ALDH5A1, GALNT12, ALG9, SCD5, PGAP1, UXS1, PCBD2, ACSS1, DGKZ, DGKD, ALG2, AGPS, B4GALT4, CBS, CDS2, SUCLG2, GMPS, ALDH1A2, ST3GAL5, MTMR2, PAPSS1, CERS5, MARS2, PIGS, PIGB, PGS1, ENTPD4, FIG4 |
hsa05200 | Pathways in cancer | 37 | 2.86 | CDK2, RASGRP2, CHUK, CRKL, AKT1, MTOR, GSTM3, MSH6, HDAC2, HSP90AB1, FAS, IKBKB, IL3RA, IL13, JAK1, LAMA5, LAMB1, SMAD2, MLH1, PIK3CD, PLCG1, PLCG2, PRKCA, MAPK9, MAP2K1, STAT5B, TGFBR1, TPR, TRAF1, TRAF3, ZBTB17, CXCR4, AXIN1, RASSF5, CASP9, CUL1, CCNE2 | ||
hsa03013 | RNA transport | 27 | 2.09 | NXF1, RPP30, POP1, EIF2B1, EIF4EBP2, NUP210, GEMIN5, CYFIP2, KPNB1, NUP88, NUP98, NUP133, NUP107, UPF1, ELAC2, TPR, UBE2I, NUP85, FXR1, THOC5, EIF3C, PABPC4, NUP155, EIF5B, TGS1, NUP93, THOC1 | ||
Up-regulated | hsa01100 | Metabolic pathways | 8 | 5.80 | AK2, LCLAT1, PGM2L1, IDS, G6PC2, GALNT14, NT5C1A, H6PD | |
hsa04010 | MAPK signaling pathway | 5 | 3.62 | DUSP1, DUSP2, FOS, JUN, STK4, STK4 | ||
has05200 | Pathways in cancer | 5 | 3.62 | FOS, DLL1, IL12A, JUN, STK4 | ||
hsa05202 | Transcriptional misregulation in cancer | 4 | 2.90 | FUS, PBX1, SS18, CCNT1 | ||
Group 2 | Down-regulated | hsa01100 | Metabolic pathways | 114 | 8.74 | NAMPT, INMT, CHKA, GPAT4, CTPS1, DGKA, DCTD, DLAT, DNMT1, EPRS, ALAS1, EXT1, ACSL3, FASN, FECH, SEPHS2, AKR1B1, GANAB, ACSL6, MLYCD, ETHE1, SHPK, PISD, KDSR, GART, GCNT1, GLDC, GLO1, GMDS, GOT2, GPI, PIGW, RIMKLA, GSTM3, HADHA, HK1, HMGCR, IDI1, INPP4A, ACADVL, STT3A, LSS, LTA4H, MAN2A2, MDH2, MPI, ASNS, NDUFA10, ATIC, NDUFB4, NDUFS1, OAT, ODC1, ACO2, OXCT1, PCCA, SEPSECS, PDE8A, PFKP, PGM1, ATP6V1B2, PIK3CD, PI4KB, PLCG1, PLCG2, PGM2, PPT1, SMPD4, CNDP2, AGK, CMAS, INPP5E, AGPAT4, QARS, BCAT1, RPN1, RPN2, SCD, GALNT11, RBKS, SGSH, SHMT1, SORD, TK2, UCK2, ALDH5A1, GALNT12, ALG9, SCD5, DGLUCY, PGAP1, UXS1, PCBD2, ACSS1, DGKZ, DGKD, ALG2, AGPS, B4GALT4, CBS, CDS2, SUCLG2, GMPS, ALDH1A2, ST3GAL5, MTMR2, PAPSS1, CERS5, MARS2, PIGS, PIGB, PGS1, ENTPD4, FIG4 |
hsa05200 | Pathways in cancer | 37 | 2.84 | CDK2, RASGRP2, CRKL, AKT1, MTOR, GSTM3, MSH6, HDAC2, HSP90AB1, FAS, IKBKB, IL3RA, IL13, JAK1, LAMA5, LAMB1, SMAD2, MLH1, PIK3CD, PLCG1, PLCG2, PRKCA, PRKCB, MAPK9, MAP2K1, STAT5B, TGFBR1, TPR, TRAF1, TRAF3, ZBTB17, CXCR4, AXIN1, RASSF5, CASP9, CUL1, CCNE2 | ||
hsa03013 | RNA transport | 27 | 2.07 | PRMT5, NXF1, RPP30, POP1, EIF2B1, EIF4EBP2, NUP210, GEMIN5, CYFIP2, KPNB1, NUP88, NUP98, NUP133, NUP107, UPF1, ELAC2, TPR, UBE2I, NUP85, FXR1, THOC5, EIF3C, PABPC4, NUP155, EIF5B, TGS1, NUP93 | ||
Up-regulated | hsa01100 | Metabolic pathways | 9 | 6.21 | CYP2C9, AK2, LCLAT1, PGM2L1, IDS, G6PC2, GALNT14, NT5C1A, H6PD | |
hsa05200 | Pathways in cancer | 6 | 4.14 | FOS, DLL1, IL12A, JUN, STK4, CCNA1 | ||
hsa04010 | MAPK signaling pathway | 5 | 3.45 | DUSP1, DUSP2, FOS, JUN, STK4 | ||
hsa05166 | Human T-cell leukemia virus 1 infection | 5 | 3.45 | EGR1, FOS, JUN, VAC14, CCNA1 |
Gene Name | Cell Lines | Main Location |
---|---|---|
SUGP1 | A-431, U-2OS, U-251MG | nucleoplasm |
DHX16 | HeLa, MCF7, U-2 OS | nucleoplasm |
FUS | A-431, U-2 OS, U-251MG | nucleoplasm |
HNRNPR | A-431, U-2 OS, U-251MG | nucleoplasm |
DHX15 | A-431, HEK 293, U-2 OS | nuclear speckles |
NAA38 | HEK 293, PC-3, U-2 OS | nucleus |
SKIV2L2 | A-431, U-2 OS, U-251MG | nucleus |
PLRG1 | A-431, U-2 OS, U-251MG | nuclear speckles, nuclear membrane |
Proteins | Species | Protein Length (aa) | Model Templates (Query Cover, Identify) |
---|---|---|---|
SUGP1 | Homo sapiens | 645 | de novo |
DHX16 | Homo sapiens | 560 | 5Z58_XX (94%, 99%) 5MQF_QQ (90%, 56%) 6FA9_A (89%, 55%) |
FUS | Homo sapiens | 522 | de novo |
HNRNPR | Homo sapiens | 535 | de novo |
DHX15 | Homo sapiens | 795 | 5XDR_A (86%, 99%) 3KX2_B (84%, 66%) 2XAU_A (84%, 66%) |
NAA38 | Homo sapiens | 125 | de novo |
SKIV2L2 | Homo sapiens | 1042 | 6D6Q_M (100%, 100%) 6C90_A (70%, 100%) 2XGJ_A (89%, 56%) |
PLRG1 | Homo sapiens | 514 | 6FF4_D (100%, 100%) 5MQF_D (100%, 99%) 4YVD_A (72%, 100%) |
Proteins | Number of Residues in Favored Region | Number of Residues in Allowed Region | Number of Residues in Disallowed Region |
---|---|---|---|
SUGP1 | 448 (93.3%) | 32 (6.7%) | 0 (0.0%) |
DHX16 | 423 (84.9%) | 65 (13.0%) | 10 (2.0%) |
FUS | 284 (82.3%) | 59 (17.1%) | 2 (0.6%) |
HNRNPR | 379 (90.2%) | 39 (9.3%) | 2 (0.5%) |
DHX15 | 658 (92.4%) | 53 (7.4%) | 1 (0.1%) |
NAA38 | 94 (89.5%) | 11 (10.5%) | 0 (0.0%) |
SKIV2L2 | 870 (93.2%) | 61 (6.5%) | 2 (0.2%) |
PLRG1 | 305 (84.3%) | 52 (14.4%) | 5 (1.4%) |
Name and Ensembl ID | Species Gene Type | Location Length | Function | Refs |
---|---|---|---|---|
SUGP1 (SURP and G-patch domain containing 1) (ENSG00000105705) | Homo sapiens Protein coding | Chr 19 (2566 bp) | A novel modulator in cholesterol metabolism | [22] |
DHX16 (DEAH-box helicase 16) (ENSG00000204560) | Homo sapiens Protein coding | Chr 6 (3406 bp) | Involved in the human pre-mRNA splicing | [23,24] |
FUS (FUS RNA binding protein) (ENSG00000089280) | Homo sapiens Protein coding | Chr 16 (5119 bp) | A key player in neuronal cell-related diseases | [25] |
HNRNPR (Heterogeneous nuclear ribonucleoprotein R) (ENSG00000125944) | Homo sapiens Protein coding | Chr 1 (7751 bp) | Is involved in processing the pre-mRNA in cell nucleus identified and is considered as a general positive modulator of MHC class I expression | [26,27] |
DHX15 (DEAH-box helicase 15) (ENSG00000109606) | Homo sapiens Protein coding | Chr 4 (2998 bp) | Is involved in the regulation of tumor cell growth, such as prostate cancer progression and bone defect regeneration | [28,29] |
NAA38 (N(alpha)-acetyltransferase 38, NatC auxiliary subunit) (ENSG00000183011) | Homo sapiens Protein coding | Chr 17 (999 bp) | Is related to the pathways of Golgi-to-ER retrograde transport and vesicle-induced transport | [30] |
SKIV2L2 (Ski2-like RNA helicase 2) (ENSG00000204351) | Homo sapiens Protein coding | Chr 6 (3795 bp) | Regulates the cell proliferation | [31] |
PLRG1 (Pleiotropic regulator 1) (ENSG00000171566) | Homo sapiens Protein coding | Chr 4 (3317 bp) | Regulates the cell proliferation | [32,33] |
Gene | GO Analysis [30] |
---|---|
SUGP1 | MF: nucleic acid binding; RNA binding; protein binding |
BP: mRNA splicing, via spliceosome; RNA processing; mRNA processing; RNA splicing | |
CC: nucleus; nucleoplasm; spliceosomal complex | |
DHX16 | MF: nucleic acid binding; RNA binding; RNA helicase activity; helicase activity; protein binding |
BP: mRNA splicing, via spliceosome; mRNA processing; RNA splicing | |
CC: nucleus; nucleoplasm; spliceosomal complex; U2-type precatalytic spliceosome | |
FUS | MF: nucleic acid binding; DNA binding; chromatin binding; transcription coactivator activity; RNA binding |
BP: mRNA splicing, via spliceosome; regulation of transcription, DNA-templated; regulation of transcription by RNA polymerase II; RNA splicing; regulation of RNA splicing | |
CC: nucleus; nucleoplasm; cytoplasm; polysome; dendrite | |
HNRNPR | MF: nucleic acid binding; RNA binding; mRNA binding; mRNA 3’-UTR binding; protein binding |
BP: nucleus; nucleoplasm; spliceosomal complex; NOT nucleolus; cytoplasm | |
CC: mRNA splicing, via spliceosome; mRNA processing; circadian rhythm; RNA splicing; RNA metabolic process | |
DHX15 | MF: nucleic acid binding; RNA binding; RNA helicase activity; double-stranded RNA binding; helicase activity |
BP: mRNA splicing, via spliceosome; mRNA processing; RNA splicing; response to toxic substance; response to alkaloid | |
CC: nucleus; nucleoplasm; U12-type spliceosomal complex; nucleolus; nuclear speck | |
NAA38 | MF: protein binding |
BP: negative regulation of apoptotic process | |
CC: nucleus; cytoplasm; colocalizes_with polysome; NatC complex | |
SKIV2L2 | MF: nucleic acid binding; RNA binding; RNA helicase activity; ATP-dependent RNA helicase activity; helicase activity |
BP: RNA catabolic process; exonucleolytic nuclear-transcribed mRNA catabolic process involved in deadenylation-dependent decay; nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay | |
CC: nucleus; cytoplasm; cytosol; Ski complex | |
PLRG1 | MF: protein binding |
BP: mRNA splicing, via spliceosome; mRNA processing; RNA splicing; protein localization to nucleus; positive regulation of G1/S transition of mitotic cell cycle | |
CC: Prp19 complex; fibrillar center; nucleus; nucleoplasm; colocalizes_with DNA replication factor A complex |
Group | Experimental Grouping |
---|---|
Group 1 | Control 30 min: Jurkat cells were cultured for 30 min (without nsPEF) Experiment 30 min: Jurkat cells were cultured for 30 min (exposed to nsPEF) |
Group 2 | Control 60 min: Jurkat cells were cultured for 60 min (without nsPEF) Experiment 60 min: Jurkat cells were cultured for 60 min (exposed to nsPEF) |
Proteins | Species | Protein Length (aa) | Model Templates (Query Cover, Identify) |
---|---|---|---|
SUGP1 | Homo sapiens | 645 | de novo |
DHX16 | Homo sapiens | 560 | 5Z58_XX (94%, 99%) 5MQF_QQ (90%, 56%) 6FA9_A (89%, 55%) |
FUS | Homo sapiens | 522 | de novo |
HNRNPR | Homo sapiens | 535 | de novo |
DHX15 | Homo sapiens | 795 | 5XDR_A (86%, 99%) 3KX2_B (84%, 66%) 2XAU_A (84%, 66%) |
NAA38 | Homo sapiens | 125 | de novo |
SKIV2L2 | Homo sapiens | 1042 | 6D6Q_M (100%, 100%) 6C90_A (70%, 100%) 2XGJ_A (89%, 56%) |
PLRG1 | Homo sapiens | 514 | 6FF4_D (100%, 100%) 5MQF_D (100%, 99%) 4YVD_A (72%, 100%) |
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Li, H.; Liu, S.; Yang, X.; Du, Y.; Luo, J.; Tan, J.; Sun, Y. Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field. Int. J. Mol. Sci. 2019, 20, 5847. https://doi.org/10.3390/ijms20235847
Li H, Liu S, Yang X, Du Y, Luo J, Tan J, Sun Y. Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field. International Journal of Molecular Sciences. 2019; 20(23):5847. https://doi.org/10.3390/ijms20235847
Chicago/Turabian StyleLi, Huijuan, Shibin Liu, Xue Yang, Yongqian Du, Jiezhang Luo, Jie Tan, and Yulong Sun. 2019. "Cellular Processes Involved in Jurkat Cells Exposed to Nanosecond Pulsed Electric Field" International Journal of Molecular Sciences 20, no. 23: 5847. https://doi.org/10.3390/ijms20235847