Meta-Analysis of Transcriptome Data Detected New Potential Players in Response to Dioxin Exposure in Humans
Abstract
:1. Introduction
2. Results
2.1. Identification of TCDD Targets in Humans
2.2. Robust TCDD Targets: Known Knowns and Known Unknowns
2.3. Search for Cis-Elements Associated with Dioxin Response
2.3.1. Unsupervised Search: No Predetermined Gene Lists and TF Binding Sites
2.3.2. Supervised Search: Robust Dioxin-Responsive Genes and Known TF Binding Sites
2.4. Composite AhR-Binding Elements Analysis
3. Discussion
3.1. Meta-Analysis of Transcriptomes
3.2. Transcriptional Regulation
3.3. Future Research
4. Materials and Methods
4.1. Datasets
4.2. Data Processing and Identification of Dioxin-Responsive Genes
4.3. Functional Annotation of Dioxin-Responsive Genes
4.4. Motif Discovery in Promoters and Peaks of Dioxin-Responsive Genes
4.5. The Search of Potential AhR Interacting Partners
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ABCG2 | ATP-binding cassette sub-family G member 2 |
ADAM12 | Disintegrin and metalloproteinase domain-containing protein 12 |
AhR | Aryl hydrocarbon receptor |
AhRR | Aryl-hydrocarbon receptor repressor |
AIP | AhR-interacting protein |
ALDH1A3 | Aldehyde dehydrogenase 1 family member A3 |
ANKRD1 | Ankyrin repeat domain-containing protein 1 |
ARNT | Aryl hydrocarbon receptor nuclear translocator |
BMF | Bcl-2-modifying factor |
BST2 | Bone marrow stromal antigen 2 |
C1S | Complement C1s subcomponent |
CA9 | Carbonic anhydrase 9 |
CABLES1 | CDK5 and ABL1 enzyme substrate 1 |
CE | Composite element |
CEBPD | CCAAT/enhancer-binding protein delta |
COLEC12 | Collectin-12 |
CPA4 | Carboxypeptidase A4 |
CRIP2 | Cysteine-rich protein 2 |
CSK | Tyrosine-protein kinase CSK |
CTCFL | CCCTC-binding factor |
CYP1A1 | Cytochrome P450 family 1 subfamily A member 1 |
CYP1B1 | Cytochrome P450 family 1 subfamily B member 1 |
DEG | Differentially expressed genes |
DHRS3 | Short-chain dehydrogenase/reductase 3 |
DKK1 | Dickkopf-1 |
E2F2 | Transcription factor E2F2 |
FAM20C | Extracellular serine/threonine protein kinase FAM20C |
FDR | False discovery rate |
FN1 | Fibronectin |
FOSL2 | Fos-related antigen 2 |
FZD7 | Frizzled-7 |
GADD45A | Growth arrest and DNA damage-inducible protein GADD45 alpha |
GALNT10 | Polypeptide N-acetylgalactosaminyltransferase 10 |
GBP2 | Guanylate-binding protein 2 |
GDF15 | Growth/differentiation factor 15 |
GEO | Gene Expression Omnibus |
GO | Gene Ontology |
Hsp90 | 90 kDa heat shock protein |
IER3 | Radiation-inducible immediate-early gene IEX-1 |
IL1R1 | Interleukin-1 receptor type 1 |
KLF | Krüppel-like factor |
LACC1 | Laccase domain-containing protein 1 |
Lif | Leukemia inhibitory factor |
LRAT | Lecithin retinol acyltransferase |
MSX2 | Homeobox protein MSX-2 |
MYC | Myc proto-oncogene protein |
NC-XRE | Non-consensus XRE |
NDRG1 | N-myc downstream-regulated gene 1 protein |
OAS1 | 2′-5′-oligoadenylate synthase 1 |
PHLDA1 | Pleckstrin homology-like domain family A member 1 |
PTGES | Prostaglandin E synthase |
PWM | Position-weighted matrix |
RA | All-trans-retinoic acid |
RUNX1 | Runt-related transcription factor 1 |
RUNX2 | Runt related transcription factor 2 |
SALL4 | Sal-like protein 4 |
SECTM1 | Secreted and transmembrane protein 1 |
Sp1 | Specificity protein 1 |
TCDD | 2,3,7,8-tetrachlorodibenzo-p-dioxin |
TIPARP | TCDD inducible poly(ADP-ribose) polymerase |
TF | Transcription factor |
XRE | Xenobiotic-responsive elements |
YPEL3 | Protein yippee-like 3 |
ZN281 | Zinc finger protein 281 |
ZBT14 | Zinc finger and BTB domain-containing protein 14 |
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№ | GEO Accession Number | Library Strategy | Platform | Time and Concentration of TCDD Treatment | Cell Culture | Replicates | References |
---|---|---|---|---|---|---|---|
1 | GSE46874 | Microarray | Affymetrix Human Gene 1.0 ST Array | 30 h, 25 nM | HepaRG cells | 3 | [14] |
2 | GSE69845 | Microarray | Affymetrix Human Genome 219U Array | 6 h, 1 nM | MCF-7 breast cancer cells | 3 | [15] |
3 | 6 h, 10 nM | MCF-7 breast cancer cells | 3 | ||||
4 | 6 h, 100 nM | MCF-7 breast cancer cells | 3 | ||||
5 | GSE69849 | Microarray | Affymetrix Human Genome 219U Array | 6 h, 1 nM | Ishikawa cells | 3 | [15] |
6 | 6 h, 10 nM | Ishikawa cells | 3 | ||||
7 | 6 h, 100 nM | Ishikawa cells | 3 | ||||
8 | GSE69850 | Microarray | Affymetrix Human Genome 219U Array | 6 h, 100 nM | HepaRG | 3 | [15] |
9 | GSE122518 | Microarray | Illumina HumanHT-12 v4.0 expression beadchip | 24 h, 1 nM | HepaRG cells | 4 | [16] |
10 | GSE63935 | RNA-Seq | Illumina HiSeq 2500 | 48 h, 3 nM | The mixture of cells: combined neural progenitor cells, endothelial cells, mesenchymal stem cells, and microglia/macrophage precursor | 2 | [17] |
11 | 144 h, 3 nM | 2 | |||||
12 | GSE98515 | RNA-Seq | Illumina HiSeq 1500 | 6 h, 10 nM | MCF-7 breast cancer cells | 4 | [18] |
13 | 6 h, 100 nM | MCF-7 breast cancer cells | 4 | ||||
14 | GSE122002 | RNA-Seq | Illumina NextSeq 500 | 96 h, 2 nM | Mel1 embryonic stem cells (before differentiation) | 2 | [19] |
15 | 96 h, 2 nM | Mel1 embryonic stem cells (2-days after of differentiation) | 2 | ||||
16 | GSE83886 | RNA-Seq | Illumina HiSeq 2500 | 504 h, 2 nM | BEAS-2B bronchial epithelial cell | 2 | [20] |
17 | 504 h, 10 nM | BEAS-2B bronchial epithelial cell | 2 | ||||
18 | GSE114552 | RNA-Seq | Illumina Genome Analyzer II | 24 h, 10 nM | CRL-4003 decidual stromal cells | 3 | - |
19 | 144 h, 10 nM | CRL-4003 decidual stromal cells | 2 | ||||
20 | GSE141711 | RNA-Seq | Illumina HiSeq 2500 | 24 h, 1 nM | HepG2 liver hepatocellular carcinoma cell | 5 | [21] |
21 | GSE90550 | ChIP-Seq | Illumina HiSeq 2500 | 24 h, 10 nM | MCF-7 breast cancer cells | 1 | [22] |
Gene Name | Full Name | Functions | TCDD Response in 20 Datasets | Association with AhR Pathway | |
---|---|---|---|---|---|
Up-Regulation | Down-Regulation | ||||
TIPARP | TCDD inducible poly(ADP-ribose) polymerase | Acts as a negative regulator of AhR by mediating mono-ADP-ribosylation of AhR | 17 | 0 | [25] |
CYP1B1 | Cytochrome P450 family 1 subfamily B member 1 | Oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, retinoid and xenobiotics | 16 | 0 | [23] |
ALDH1A3 | Aldehyde dehydrogenase 1 family member A3 | Required for the biosynthesis of retinoic acid in the embryonic ocular and nasal regions | 15 | 0 | [26] |
CYP1A1 | Cytochrome P450 family 1 subfamily A member 1 | Oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics | 15 | 0 | [23] |
AhRR | Aryl-hydrocarbon receptor repressor | Mediates dioxin toxicity and is involved in regulation of cell growth and differentiation. Represses the transcription activity of AhR | 15 | 0 | [27] |
NFE2L2 (NRF2) | Nuclear factor erythroid 2-related factor 2 | Transcription factor that plays a key role in the response to oxidative stress: binds to antioxidant response elements present in the promoter region of many cytoprotective genes, and promotes their expression, thereby neutralizing reactive electrophiles | 15 | 0 | [28] |
RUNX2 | Runt related transcription factor 2 | Transcription factor involved in osteoblastic differentiation and skeletal morphogenesis | 14 | 1 | [29] |
SLC7A5 (LAT1) | Large neutral amino acids transporter small subunit 1; L-type amino acid transporter 1 | The heterodimer with SLC3A2 functions as a sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, L-DOPA, leucine, histidine, methionine, and tryptophan | 14 | 1 | [18] |
DKK1 | Dickkopf-1 | Locally inhibits Wnt-regulated developmental processes such as limb development, somitogenesis, and eye formation. In adults, Dkk1 is implicated in bone formation and bone disease, cancer, and Alzheimer disease | 1 | 11 | [30] |
Gene Name | Full Name | Functions | TCDD Response in 20 Datasets | |
---|---|---|---|---|
Up-Regulation | Down-Regulation | |||
IER3 | Radiation-inducible immediate-early gene IEX-1 | May play a role in the ERK signaling pathway by inhibiting the dephosphorylation of ERK. Acts also as an ERK downstream effector mediating survival | 13 | 0 |
SECTM1 | Secreted and transmembrane protein 1 | May be involved in thymocyte signaling | 12 | 0 |
PHLDA1 | Pleckstrin homology-like domain family A member 1 | Seems to be involved in the regulation of apoptosis | 12 | 0 |
SLC7A11 (xCT) | Cystine/glutamate transporter | Sodium-independent, high-affinity exchange of anionic amino acids with high specificity for an anionic form of cysteine and glutamate | 12 | 1 |
RUNX1 | Runt-related transcription factor 1 | Forms the heterodimeric complex core-binding factor (CBF) with CBFB. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, etc. Essential for hematopoiesis | 11 | 1 |
EDC3 | Enhancer of mRNA-decapping protein 3 | Binds single-stranded RNA. Involved in the process of mRNA degradation and in the positive regulation of mRNA decapping | 11 | 0 |
TPRA1 | Transmembrane protein adipocyte-associated 1 | Regulates early mouse embryogenesis [31] | 11 | 0 |
TTC39C | Tetratricopeptide repeat protein 39C | Appears to be necessary for proper MAP Kinase and Hedgehog signal transduction in developing muscle cells, as well as muscle cell differentiation [32] | 11 | 0 |
VIPR1 | Vasoactive intestinal polypeptide receptor 1 | A receptor for VIP. The activity of this receptor is mediated by G proteins that activate adenylyl cyclase | 10 | 0 |
GAD1 | Glutamate decarboxylase 1 | Catalyzes the production of GABA | 10 | 1 |
TF Binding Sites | Upstream Regions of Dioxin−Regulated Genes | Composite Elements in AhR-Binding Regions | |
---|---|---|---|
MetaRE | HOMER | MCOT | |
AhR | + * | + | + |
ARNT | − | + | + |
E2F2 | − | + | + |
KLF12 | + | + | − |
CTCFL | + | + | − |
Sp1 | + | + | − |
ZBT14 | + | + | + |
ZNF281 | + | + | − |
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Oshchepkova, E.; Sizentsova, Y.; Wiebe, D.; Mironova, V.; Kolchanov, N. Meta-Analysis of Transcriptome Data Detected New Potential Players in Response to Dioxin Exposure in Humans. Int. J. Mol. Sci. 2020, 21, 7858. https://doi.org/10.3390/ijms21217858
Oshchepkova E, Sizentsova Y, Wiebe D, Mironova V, Kolchanov N. Meta-Analysis of Transcriptome Data Detected New Potential Players in Response to Dioxin Exposure in Humans. International Journal of Molecular Sciences. 2020; 21(21):7858. https://doi.org/10.3390/ijms21217858
Chicago/Turabian StyleOshchepkova, Evgeniya, Yana Sizentsova, Daniil Wiebe, Victoria Mironova, and Nikolay Kolchanov. 2020. "Meta-Analysis of Transcriptome Data Detected New Potential Players in Response to Dioxin Exposure in Humans" International Journal of Molecular Sciences 21, no. 21: 7858. https://doi.org/10.3390/ijms21217858