RNA-Seq Analysis Reveals an Essential Role of the Tyrosine Metabolic Pathway and Inflammation in Myopia-Induced Retinal Degeneration in Guinea Pigs
Abstract
:1. Introduction
2. Results
2.1. Refraction Error and Ocular Parameters in Form-Deprivation Induced Myopia
2.2. Electroretinogram Response in FDM and Control Eyes
2.3. Immunohistochemistry of Retinal Neurons in FDM and Control Eyes
2.3.1. Photoreceptors
2.3.2. Bipolar Cells and Synapses in Outer Plexiform Layer
2.3.3. Horizontal Cells, Amacrine and Retinal Ganglion Cells
2.3.4. Retinal Müller Glia and Microglial Cells
2.4. RNA-Sequencing Analysis of Molecular Changes in Myopic Retina
3. Discussion
4. Materials and Methods
4.1. Animals
4.2. Form Deprivation-Induced Myopia
4.3. Measurement of Refractive Error and Ocular Biometrics
4.4. Electroretinography
4.5. Immunofluorescence
4.6. Morphological Analysis of Retinal Cells
4.7. RNA Sequencing
4.8. Quantitative Real-Time PCR (qRT-PCR)
4.9. Other Data Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Antigen | Host | Product ID | Dilution | Source | Cell Location |
---|---|---|---|---|---|
Primary Antibodies | |||||
Peanut agglutinin(PNA)-Biotin | - | 019-19741 | 1:500 | Sigma | Cone photoreceptors |
Rhodopsin | Mouse | MAB5356 | 1:500 | Millipore | Rod photoreceptors |
Bassoon | Mouse | SAP7F407 | 1:50 | Invitrogen | Synaptic ribbons |
Secretagogin (SCGN) | Rabbit | HPA006641 | 1:100 | Sigma | Cone bipolar cells |
PKCα | Mouse | Sc-8393 | 1:300 | Santa Cruz | Rod bipolar cells |
Calbindin | Rabbit | TA342845 | 1:50 | Origene | Horizontal cells |
c-aminobutyric acid (GABA) | Rabbit | 20094 | 1:200 | Immunostar | GABAergic amacrine cells |
Choline Acetyltransferase | Goat | AB144P | 1:100 | Millipore | CHATergic amacrine cells |
RBPMS | Rabbit | Ab194213 | 1:500 | Abcam | Retinal ganglion cells |
GFAP | Mouse | MCA4734GA | 1:300 | Bio-Rad | Muller cells |
IBA-1 | Rabbit | 019-19741 | 1:300 | Bio-Rad | Microglial cells |
Secondary antibodies | |||||
Anti-mouse IgG (H+L), Alexa Fluor 594 | Goat | A-11005 | 1:500 | Invitrogen | |
Anti-rabbit IgG (H+L), Alexa Fluor 488 | Goat | A-11034 | 1:500 | Invitrogen | |
Anti-goat IgG (H+L), Alexa Fluor 647 | Donkey | A-21447 | 1:500 | Invitrogen | |
Streptavidin-Daylight 594 | - | ZF1010 | 1:500 | Vector Laboratories |
Pathway | No of DEGs | P Value |
---|---|---|
Immune Responses | ||
AGE-RAGE signaling pathway | 9 | 0.0001 |
Complement and coagulation cascades | 7 | 0.001 |
Phagosome | 11 | 0.004 |
Platelet activation | 8 | 0.007 |
Amoebiasis | 9 | 0.008 |
Cell adhesion molecules (CAMs) | 9 | 0.009 |
Antigen processing and presentation | 6 | 0.012 |
Pertussis | 5 | 0.014 |
Viral myocarditis | 8 | 0.014 |
Malaria | 5 | 0.017 |
NOD-like receptor signaling pathway | 8 | 0.019 |
Influenza A | 8 | 0.020 |
Staphylococcus aureus infection | 8 | 0.025 |
HTLV-I infection | 10 | 0.027 |
Cytosolic DNA-sensing pathway | 4 | 0.030 |
African trypanosomiasis | 5 | 0.038 |
Hematopoietic cell lineage | 7 | 0.041 |
Inflammatory mediator regulation of TRP channels | 5 | 0.041 |
Systemic lupus erythematosus | 8 | 0.042 |
Human cytomegalovirus infection | 9 | 0.042 |
IL-17 signaling pathway | 5 | 0.044 |
Cellular metabolism | ||
ABC transporters | 5 | 0.003 |
Protein digestion and absorption | 7 | 0.003 |
Arachidonic acid metabolism | 5 | 0.008 |
alpha-linolenic acid metabolism | 3 | 0.014 |
Regulation of actin cytoskeleton | 9 | 0.018 |
Linoleic acid metabolism | 3 | 0.022 |
Tyrosine metabolism | 3 | 0.023 |
Thiamine metabolism | 2 | 0.027 |
Retinol metabolism | 4 | 0.027 |
Cardiovascular function | ||
Vascular smooth muscle contraction | 11 | 0.000 |
Renin-angiotensin system | 4 | 0.001 |
Others | ||
Neuroactive ligand–receptor interaction | 12 | 0.023 |
Apelin signaling pathway | 6 | 0.046 |
Pathway | No. of DEGs | P Value |
---|---|---|
Inflammatory Responses | ||
AGE-RAGE signaling pathway | 9 | 0.00002 |
Complement and coagulation cascades | 7 | 0.0002 |
Amoebiasis | 9 | 0.001 |
NOD-like receptor signaling pathway | 8 | 0.004 |
Influenza A | 8 | 0.004 |
Pertussis | 5 | 0.005 |
Staphylococcus aureus infection | 8 | 0.006 |
Malaria | 5 | 0.006 |
Systemic lupus erythematosus | 8 | 0.010 |
Hematopoietic cell lineage | 7 | 0.011 |
Cytosolic DNA-sensing pathway | 4 | 0.013 |
Phospholipase D signaling pathway | 8 | 0.013 |
African trypanosomiasis | 5 | 0.014 |
IL-17 signaling pathway | 5 | 0.016 |
Rheumatoid arthritis | 7 | 0.021 |
Platelet activation | 6 | 0.021 |
Fc gamma R-mediated phagocytosis | 6 | 0.025 |
TNF signaling pathway | 5 | 0.035 |
Fc epsilon RI signaling pathway | 5 | 0.040 |
Phagosome | 7 | 0.046 |
Cellular metabolism | ||
ABC transporters | 4 | 0.007 |
Tyrosine metabolism | 3 | 0.012 |
Thyroid hormone signaling pathway | 5 | 0.032 |
Choline metabolism in cancer | 4 | 0.049 |
Cardiovascular function | ||
Renin-angiotensin system | 4 | 0.000 |
Vascular smooth muscle contraction | 7 | 0.003 |
Renin secretion | 4 | 0.025 |
Dilated cardiomyopathy (DCM) | 6 | 0.031 |
Regulation of actin cytoskeleton | 7 | 0.033 |
Hypertrophic cardiomyopathy (HCM) | 4 | 0.049 |
Apelin signaling pathway | 5 | 0.050 |
Pathway | No of DEGs | P Value |
---|---|---|
Metabolic Pathways | ||
Retinol metabolism | 3 | 0.002 |
Arachidonic acid metabolism | 3 | 0.003 |
Type I diabetes mellitus | 3 | 0.006 |
alpha-Linolenic acid metabolism | 2 | 0.006 |
Linoleic acid metabolism | 2 | 0.008 |
Glycerophospholipid metabolism | 3 | 0.009 |
Protein digestion and absorption | 3 | 0.010 |
Fat digestion and absorption | 2 | 0.016 |
Tryptophan metabolism | 2 | 0.018 |
Metabolic pathways | 12 | 0.020 |
Ether lipid metabolism | 2 | 0.020 |
Caffeine metabolism | 1 | 0.026 |
Steroid hormone biosynthesis | 2 | 0.041 |
Inflammatory responses | ||
Graft-versus-host disease | 3 | 0.004 |
Antigen processing and presentation | 3 | 0.009 |
Phagosome | 4 | 0.017 |
Human papillomavirus infection | 5 | 0.022 |
Allograft rejection | 3 | 0.026 |
Autoimmune thyroid disease | 3 | 0.033 |
Cell adhesion molecules (CAMs) | 3 | 0.048 |
Cardiovascular function | ||
Vascular smooth muscle contraction | 4 | 0.003 |
Viral myocarditis | 3 | 0.037 |
Senescence and proliferation | ||
Cellular senescence | 4 | 0.006 |
Chemical carcinogenesis | 2 | 0.036 |
Enriched Pathways by Upregulated DEGs | ||
---|---|---|
Pathway | No of DEGs | P Value |
Inflammatory responses | ||
Hematopoietic cell lineage | 6 | 0.003 |
Staphylococcus aureus infection | 6 | 0.004 |
African trypanosomiasis | 4 | 0.009 |
Amoebiasis | 5 | 0.018 |
Rheumatoid arthritis | 5 | 0.021 |
Asthma | 4 | 0.022 |
PI3K-Akt signaling pathway | 8 | 0.027 |
Malaria | 3 | 0.028 |
Intestinal immune network for IgA production | 4 | 0.032 |
Leishmaniasis | 4 | 0.034 |
ECM-receptor interaction | 3 | 0.036 |
Phagosome | 5 | 0.040 |
Fc gamma R-mediated phagocytosis | 4 | 0.040 |
TGF-beta signaling pathway | 3 | 0.043 |
Wnt signaling pathway | 4 | 0.044 |
Cellular metabolism | ||
Tyrosine metabolism | 3 | 0.002 |
Retinol metabolism | 3 | 0.014 |
Cardiovascular function | ||
Regulation of actin cytoskeleton | 6 | 0.008 |
Renin-angiotensin system | 2 | 0.019 |
Dilated cardiomyopathy (DCM) | 4 | 0.046 |
Enriched pathways by downregulated DEGs | ||
Pathway | No of DEGs | p value |
Tight junction | 2 | 0.009 |
Salmonella infection | 2 | 0.010 |
Glycosaminoglycan biosynthesis | 1 | 0.015 |
Pathogenic Escherichia coli infection | 2 | 0.015 |
Naïve Control vs. Self-Control: Upregulated Pathways | ||
---|---|---|
Pathways | P Value | Genes |
Necroptosis | 0.003 | ENSCPOG00000026565(RIPK3); ENSCPOG0000013435(PLA2G4E); ENSCPOG00000032734(PYCARD); ENSCPOG00000007538(-) |
GnRH signaling pathway | 0.004 | ENSCPOG00000010721(PLD1); ENSCPOG00000015538(GNRH1); ENSCPOG00000013435(PLA2G4E) |
Choline metabolism in cancer | 0.005 | ENSCPOG00000010721(PLD1); ENSCPOG00000004913(SLC22A4); ENSCPOG00000013435(PLA2G4E) |
Base excision repair | 0.010 | ENSCPOG00000004970(-); ENSCPOG00000007538(-) |
Vasopressin-regulated water reabsorption | 0.013 | ENSCPOG00000004446(AQP4); ENSCPOG00000000298(ARHGDIB) |
Ether lipid metabolism | 0.014 | ENSCPOG00000010721(PLD1); ENSCPOG00000013435(PLA2G4E) |
Neomycin, kanamycin and gentamicin biosynthesis | 0.018 | ENSCPOG00000010344(HK3) |
Cytosolic DNA-sensing pathway | 0.022 | ENSCPOG00000026565(RIPK3); ENSCPOG00000032734(PYCARD) |
Arachidonic acid metabolism | 0.024 | ENSCPOG00000034340(-); ENSCPOG00000013435(PLA2G4E) |
Legionellosis | 0.024 | ENSCPOG00000032734(PYCARD); ENSCPOG00000033682(HSPA6) |
Sulfur relay system | 0.029 | ENSCPOG00000039069(URM1) |
Phospholipase D signaling pathway | 0.044 | ENSCPOG00000023212(AGT); ENSCPOG00000010721(PLD1); ENSCPOG00000013435(PLA2G4E) |
Hypertrophic cardiomyopathy (HCM) | 0.048 | ENSCPOG00000011275(-); ENSCPOG00000023212(AGT) |
Naïve control vs. self-control: Downregulated pathways | ||
Pathways | p value | Genes |
Insulin resistance | 0.007 | ENSCPOG00000013545(CREB5); ENSCPOG00000031830(SLC2A4); ENSCPOG00000002439(SREBF1) |
Viral carcinogenesis | 0.008 | ENSCPOG00000001300(-); ENSCPOG00000013545(CREB5); ENSCPOG00000012203(-); MSTRG.24368(Patr-A) |
Human papillomavirus infection | 0.010 | ENSCPOG00000001300(-); ENSCPOG00000013545(CREB5); ENSCPOG00000025029(COMP); ENSCPOG00000032331(CHAD); MSTRG.24368(Patr-A) |
AMPK signaling pathway | 0.011 | ENSCPOG00000013545(CREB5); ENSCPOG00000031830(SLC2A4); ENSCPOG00000002439(SREBF1) |
HTLV-I infection | 0.015 | ENSCPOG00000001300(-); ENSCPOG00000013545(CREB5); ENSCPOG00000012203(-); MSTRG.24368(Patr-A) |
Retinol metabolism | 0.021 | ENSCPOG00000015596(CYP1A1); ENSCPOG00000021751(CYP26A1) |
Caffeine metabolism | 0.022 | ENSCPOG00000019452(-) |
Cellular senescence | 0.023 | ENSCPOG00000001300(-); ENSCPOG00000022941(-); MSTRG.24368(Patr-A) |
Chemical carcinogenesis | 0.026 | ENSCPOG00000015596(CYP1A1); ENSCPOG00000019452(-) |
Graft-versus-host disease | 0.030 | ENSCPOG00000001300(-); MSTRG.24368(Patr-A) |
Type I diabetes mellitus | 0.038 | ENSCPOG00000001300(-); MSTRG.24368(Patr-A) |
ECM-receptor interaction | 0.041 | ENSCPOG00000025029(COMP); ENSCPOG00000032331(CHAD) |
Phagosome | 0.050 | ENSCPOG00000001300(-); ENSCPOG00000025029(COMP); MSTRG.24368(Patr-A) |
Appendix B
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Axial Length (mm) | Vitreous Chamber Depth (mm) | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Weeks | 0 | 3 | 7 | 9 | 12 | 15 | 0 | 3 | 7 | 9 | 12 | 15 |
Control | 7.85 ± 0.10 | 8.14 ± 0.16 | 8.54 ± 0.13 | 8.63 ± 0.07 | 8.72 ± 0.07 | 8.74 ± 0.09 | 3.11 ± 0.05 | 3.13 ± 0.05 | 3.16 ± 0.05 | 3.18 ± 0.06 | 3.19 ± 0.06 | 3.20 ± 0.06 |
Self-Control | 7.89 ± 0.21 | 8.12 ± 0.18 | 8.47 ± 0.27 | 8.54 ± 0.18 | 8.68 ± 0.18 | 8.68 ± 0.15 | 3.10 ± 0.11 | 3.12 ± 0.10 | 3.15 ± 0.13 | 3.13 ± 0.14 | 3.15 ± 0.10 | 3.13 ± 0.10 |
FDM | 7.85 ± 0.15 | 8.35 ± 0.17 * | 8.74 ± 0.24 | 8.86 ± 0.22 * | 9.06 ± 0.23 * | 9.12 ± 0.24 * | 3.10 ± 0.06 | 3.27 ± 0.12 * | 3.40 ± 0.20 * | 3.45 ± 0.18 * | 3.53 ± 0.22 * | 3.51 ± 0.22 * |
Refractive Error (D) | Corneal Curvature Radius (mm) | |||||||
---|---|---|---|---|---|---|---|---|
Weeks | 0 | 3 | 7 | 9 | 12 | 15 | 0 | 15 |
Control | 3.80 ± 0.81 | 2.93 ± 1.18 | 3.02 ± 0.56 | 3.06 ± 1.10 | 2.40 ± 0.73 | 2.69 ± 0.56 | 3.43 ± 0.08 | 3.91 ± 0.09 |
Self-Control | 3.08 ± 1.04 | 2.79 ± 1.24 | 2.49 ± 1.20 | 2.03 ± 0.73 | 2.18 ± 0.89 | 2.94 ± 0.59 | 3.45 ± 0.09 | 3.87 ± 0.12 |
FDM | 2.94 ± 1.47 | 1.35 ± 1.87 * | 0.38 ± 2.89 * | −0.66 ± 2.51 * | −2.28 ± 2.22 * | −3.40 ± 1.85 * | 3.44 ± 0.08 | 3.92 ± 0.13 |
Top 15 Upregulated Genes | Top 15 Downregulated Genes | ||||||
---|---|---|---|---|---|---|---|
Symbol | Log2(fc) | P Value | Description | Symbol | Log2(fc) | P Value | Description |
WAS | 7.229 | 0.041 | WASP actin nucleation promoting factor | BATF | −8.077 | 0.030 | BATF |
TECRL | 6.748 | 0.046 | Trans-2,3-enoyl-CoA reductase like | PHF23 | −7.570 | 0.003 | PHD finger protein 23 |
SIX1 | 4.807 | 0.005 | SIX homeobox 1 | SLC2A8 | −4.382 | 0.011 | Solute carrier family 2, facilitated glucose transporter member 8-like |
FCN1 | 4.605 | 0.006 | Ficolin 1 | FAM186B | −4.115 | 0.031 | Family with sequence similarity 186 member B |
SLC22A4 | 4.322 | 0.023 | Solute carrier family 22 member 4 | ALDH8A1 | −3.907 | 0.015 | Aldehyde dehydrogenase 8 family member A1 |
TIE1 | 4.209 | 0.016 | Tyrosine kinase with immunoglobulin like and EGF like domains 1 | DCST1 | −3.719 | 0.022 | DC-STAMP domain containing 1 |
S100A9 | 4.115 | 0.019 | S100 calcium binding protein A9 | VMO1 | −3.700 | 0.019 | Vitelline membrane outer layer 1 homolog |
S100A11 | 3.886 | 0.021 | S100 calcium binding protein A11] | Pol | −3.143 | 0.002 | LORF2 protein, partial |
GZMK | 3.652 | 0.029 | Granzyme K | IFITM5 | −2.839 | 0.015 | Interferon induced transmembrane protein 5 |
NLRC5 | 3.649 | 0.034 | NLR family CARD domain containing 5 | SAMD13 | −2.807 | 0.028 | Sterile alpha motif domain containing 13 |
RIPK3 | 3.629 | 0.014 | Receptor interacting serine/threonine kinase 3 | CRYBA2 | −2.641 | 0.003 | Crystallin beta A2 |
TGM7 | 3.502 | 0.000 | Transglutaminase 7 | ACOT12 | −2.558 | 0.014 | Acyl-CoA thioesterase 12 |
SLC9C1 | 3.492 | 0.013 | Solute carrier family 9 member C1 | MYH8 | −2.466 | 0.000 | Myosin heavy chain 8 |
IDO1 | 3.433 | 0.010 | Indoleamine 2,3-dioxygenase 1 | GRAMD2A | −2.459 | 0.004 | GRAM domain containing 2A |
CHP2 | 3.426 | 0.020 | Calcineurin like EF-hand protein 2 | CHAD | −2.415 | 0.017 | Chondroadherin |
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Zeng, L.; Li, X.; Liu, J.; Liu, H.; Xu, H.; Yang, Z. RNA-Seq Analysis Reveals an Essential Role of the Tyrosine Metabolic Pathway and Inflammation in Myopia-Induced Retinal Degeneration in Guinea Pigs. Int. J. Mol. Sci. 2021, 22, 12598. https://doi.org/10.3390/ijms222212598
Zeng L, Li X, Liu J, Liu H, Xu H, Yang Z. RNA-Seq Analysis Reveals an Essential Role of the Tyrosine Metabolic Pathway and Inflammation in Myopia-Induced Retinal Degeneration in Guinea Pigs. International Journal of Molecular Sciences. 2021; 22(22):12598. https://doi.org/10.3390/ijms222212598
Chicago/Turabian StyleZeng, Ling, Xiaoning Li, Jian Liu, Hong Liu, Heping Xu, and Zhikuan Yang. 2021. "RNA-Seq Analysis Reveals an Essential Role of the Tyrosine Metabolic Pathway and Inflammation in Myopia-Induced Retinal Degeneration in Guinea Pigs" International Journal of Molecular Sciences 22, no. 22: 12598. https://doi.org/10.3390/ijms222212598