Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes
Abstract
:1. Introduction
2. Results
2.1. Selection of Genes for Prioritization
2.2. Gene Prioritization
2.2.1. Differential Expression in POAG-Affected Human TM Tissue or SC Cells
2.2.2. High Expression in RNA-Seq of Primary Human TM and SC Cells
2.2.3. High Expression in Human Ocular Tissue
2.2.4. Variant Impacts on Expression Due to Location in Regulatory Regions
2.2.5. Differential Expression in Cyclically Stretched Primary Human TM Cells
2.2.6. Differential Expression in Outflow Pathway scRNA-Seq
2.2.7. Differential Expression Correlation Analysis
2.3. Estrogen Signaling in the Human Outflow Pathway
3. Discussion
3.1. Overview
3.2. IOP-Associated Gene Prioritization
3.3. Estrogen Signaling in IOP Regulation
3.4. Limitations and Future Work
3.5. Conclusions
4. Materials and Methods
4.1. Gene Prioritization Using RNA-Sequencing and Previously Published Datasets
4.2. Differential Expression Correlation and Network Analyses
4.3. Reagents
4.4. RNA-Sequencing
4.5. Aqueous Humor Estradiol Quantification
4.6. Quantitative Real-Time PCR
4.7. Immunofluorescence
4.8. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | Description | Fold Change | p |
---|---|---|---|
ANKH | ANKH inorganic pyrophosphate transport regulator | 2.69 | 3.16 × 10-7 |
ANTXR1 | ANTXR cell adhesion molecule 1 | 1.79 | 6.46 × 10-3 |
COL8A2 | Collagen type VIII α2 chain | 2.66 | 1.32 × 10-4 |
EFEMP1 | EGF containing fibulin extracellular matrix protein 1 | 1.82 | 4.43 × 10-3 |
GMDS | GDP-mannose 4,6-dehydratase | 1.93 | 3.14 × 10-3 |
HLA-DQA1 | Major histocompatibility complex, class II, DQ α1 | 2.13 | 3.10 × 10-3 |
LTBP2 | Latent TGF-β binding protein 2 | 2.25 | 1.65 × 10-3 |
MAFB | MAF BZIP transcription factor B | 1.54 | 1.22 × 10-2 |
RPLP2 | Ribosomal protein lateral stalk subunit P2 | 1.58 | 1.32 × 10-1 |
SEMA3E | Semaphorin 3E | 1.94 | 1.26 × 10-5 |
Gene | Description | Fold Change | p |
---|---|---|---|
AFAP1 | Actin filament associated protein 1 | 1.56 | 1.35 × 10−1 |
ANGPTL2 | Angiopoietin like 2 | −3.33 | 6.73 × 10−2 |
ANTXR1 | ANTXR cell adhesion molecule 1 | −1.67 | 4.77 × 10−2 |
COL4A1 | Collagen type IV α1 chain | 2.84 | 1.43 × 10−1 |
CPXM1 | Carboxypeptidase X, M14 family member 1 | 1.57 | 2.18 × 10−2 |
ETS1 | ETS proto-oncogene 1, transcription factor | 1.61 | 1.28 × 10−1 |
HHEX | Hematopoietically expressed homeobox | −1.62 | 1.81 × 10−2 |
LTBP2 | Latent TGF-β binding protein 2 | −1.63 | 1.56 × 10−1 |
MAFB | MAF BZIP transcription factor B | −1.79 | 2.82 × 10−1 |
ME3 | Malic enzyme 3 | −1.59 | 3.23 × 10−3 |
NR1H3 | Nuclear receptor subfamily 1 group H member 3 | −1.59 | 5.54 × 10−2 |
PCSK5 | Proprotein convertase subtilisin/kexin type 5 | −2.04 | 3.93 × 10−2 |
PRKAG2 | Protein kinase AMP-activated non-catalytic subunit γ2 | 1.63 | 1.70 × 10−2 |
PRSS23 | Serine protease 23 | −1.65 | 1.60 × 10−1 |
PTPN1 | Protein tyrosine phosphatase non-receptor type 1 | 1.63 | 1.63 × 10−2 |
SH2B3 | SH2B adaptor protein 3 | 1.58 | 7.07 × 10−3 |
TES | Testin LIM domain protein | 1.54 | 4.75 × 10−2 |
Gene | Cell/Tissue Type | RNA-Seq Expression (FPKM) |
---|---|---|
AFAP1 | SC | 46.64 |
ANGPTL2 | SC | 30.90 |
ANKH | TM | 64.41 |
ANTXR1 * | TM, SC | 32.78, 47.13 |
COL4A1 | SC | 17.92 |
COL8A2 | TM | 34.44 |
CPXM1 | SC | 0.49 |
EFEMP1 | TM | 89.70 |
ETS1 | SC | 15.70 |
GMDS | TM | 29.40 |
HHEX | SC | 2.60 |
HLA-DQA1 | TM | 0.00 |
LTBP2 * | TM, SC | 104.70, 171.74 |
MAFB * | TM, SC | 1.37, 1.79 |
ME3 | SC | 11.09 |
NR1H3 | SC | 4.45 |
PCSK5 | SC | 1.97 |
PRKAG2 | SC | 6.49 |
PRSS23 | SC | 184.92 |
PTPN1 | SC | 12.46 |
RPLP2P1 | TM | 0.00 |
SEMA3E | TM | 1.51 |
SH2B3 | SC | 13.63 |
TES | SC | 64.48 |
Gene | Trabecular Meshwork | Ciliary Body | Cornea | ||||||
---|---|---|---|---|---|---|---|---|---|
PLIER | DABG Average | DABG Range | PLIER | DABG Average | DABG Range | PLIER | DABG Average | DABG Range | |
AFAP1 | 33.64 | 0.08 | 0–0.58 | 31.53 | 0.07 | 0–0.49 | 30.54 | 0.14 | 0–0.77 |
ANGPTL2 | 45.11 | 0.16 | 0–0.71 | 30.32 | 0.19 | 0–0.8 | 74.34 | 0.07 | 0–0.42 |
ANKH | 112.61 | 0.05 | 0–0.76 | 70.15 | 0.05 | 0–0.51 | 88.56 | 0.07 | 0–0.51 |
ANTXR1 * | 145.19 | 0.06 | 0–0.89 | 90.84 | 0.10 | 0–0.77 | 58.56 | 0.09 | 0–0.84 |
COL4A1 | 46.71 | 0.08 | 0–0.92 | 42.61 | 0.16 | 0–0.97 | 24.59 | 0.24 | 0–0.98 |
COL8A2 | 99.82 | 0.12 | 0–0.56 | 86.39 | 0.14 | 0–0.52 | 81.40 | 0.11 | 0–0.57 |
CPXM1 | 26.48 | 0.11 | 0–0.58 | 24.60 | 0.17 | 0–0.85 | 26.29 | 0.10 | 0–0.32 |
EFEMP1 | 214.28 | 0.01 | 0–0.11 | 667.78 | 0.03 | 0–0.35 | 165.29 | 0.04 | 0–0.52 |
ETS1 | 86.82 | 0.07 | 0–0.76 | 41.16 | 0.08 | 0–0.51 | 27.07 | 0.05 | 0–0.35 |
GMDS | 76.23 | 0.06 | 0–0.20 | 88.91 | 0.19 | 0–0.78 | 93.19 | 0.06 | 0–0.16 |
HHEX | 92.41 | 0.14 | 0–0.64 | 63.12 | 0.20 | 0–0.54 | 95.97 | 0.23 | 0–0.95 |
HLA-DQA1 | NA | NA | NA | NA | NA | NA | NA | NA | NA |
LTBP2 * | 79.44 | 0.06 | 0–0.66 | 69.94 | 0.08 | 0–0.77 | 62.10 | 0.08 | 0–0.53 |
MAFB * | 54.38 | 0.19 | 0–0.93 | 62.34 | 0.17 | 0–0.82 | 77.52 | 0.09 | 0–0.50 |
ME3 | 29.17 | 0.13 | 0–0.86 | 36.24 | 0.17 | 0–0.52 | 34.63 | 0.11 | 0–0.52 |
NR1H3 | 32.84 | 0.18 | 0–0.72 | 32.88 | 0.23 | 0–1.00 | 33.11 | 0.16 | 0–0.57 |
PCSK5 | 37.87 | 0.07 | 0–0.33 | 31.31 | 0.17 | 0–0.81 | 234.57 | 0.01 | 0–0.18 |
PRKAG2 | 65.93 | 0.08 | 0–0.68 | 57.75 | 0.14 | 0–0.78 | 51.41 | 0.13 | 0–0.72 |
PRSS23 | 76.78 | 0.06 | 0–0.34 | 155.24 | 0.02 | 0–0.15 | 121.46 | 0.04 | 0–0.28 |
PTPN1 | 84.10 | 0.02 | 0–0.22 | 61.15 | 0.06 | 0–0.62 | 78.01 | 0.07 | 0–0.37 |
RPLP2P1 | NA | NA | NA | NA | NA | NA | NA | NA | NA |
SEMA3E | 130.67 | 0.01 | 0–0.20 | 28.40 | 0.10 | 0–0.82 | 35.46 | 0.07 | 0–0.83 |
SH2B3 | 40.00 | 0.15 | 0–0.99 | 29.77 | 0.15 | 0–0.68 | 37.72 | 0.12 | 0–0.5 |
TES | 290.39 | 0.01 | 0–0.11 | 67.06 | 0.07 | 0–0.27 | 193.21 | 0.01 | 0–0.08 |
Gene | Trabecular Meshwork | Ciliary Body | Cornea |
---|---|---|---|
AFAP1 | 3.10 | 4.71 | 2.46 |
ANGPTL2 | 18.84 | 15.75 | 8.69 |
ANKH | 50.88 | 32.83 | 21.43 |
ANTXR1 * | 67.92 | 5.40 | 10.42 |
COL4A1 | 9.15 | 8.06 | 0.73 |
COL8A2 | 118.54 | 33.40 | 28.26 |
CPXM1 | 6.63 | 9.52 | 0.22 |
EFEMP1 | 142.27 | 153.01 | 77.16 |
ETS1 | 16.18 | 1.85 | 3.56 |
GMDS | 81.59 | 55.42 | 89.55 |
HHEX | 2.25 | 0.53 | 0.48 |
HLA-DQA1 | 31.13 | 4.11 | 9.36 |
LTBP2 * | 54.69 | 142.61 | 3.93 |
MAFB * | 13.35 | 1.45 | 8.08 |
ME3 | 7.26 | 15.74 | 5.42 |
NR1H3 | 8.60 | 19.88 | 7.02 |
PCSK5 | 5.04 | 2.71 | 21.57 |
PRKAG2 | 16.79 | 2.30 | 16.08 |
PRSS23 | 23.22 | 8.20 | 16.50 |
PTPN1 | 16.16 | 34.22 | 17.24 |
RPLP2P1 | 0.00 | 0.00 | 0.00 |
SEMA3E | 8.27 | 0.16 | 1.93 |
SH2B3 | 4.54 | 2.79 | 1.28 |
TES | 56.81 | 0.81 | 30.17 |
SNP | Gene | Histone Modification | Enhancer or Promoter Region | Significant eQTL |
---|---|---|---|---|
rs28649910 | AFAP1 | Yes | Yes | Skin; Whole blood |
rs11795066 | ANGPTL2 | Yes | No | Cerebellum; Esophageal mucosa; Skin; Testis; Tibial nerve; Thyroid; Whole blood |
rs368503 | ANKH | Yes | No | Esophageal mucosa |
rs6546486 | ANTXR1 * | Yes | Yes | None |
rs112972174 | COL4A1 | Yes | Yes | None |
rs12123086 | COL8A2 | Yes | Yes | Whole blood |
rs4672075 | EFEMP1 | Yes | No | Skin; Thyroid |
rs7924522 | ETS1 | Yes | Yes | None |
rs722585 | GMDS | Yes | No | None |
rs74384554 | LTBP2 * | Yes | No | Tibial nerve |
rs2433414 | ME3 | Yes | Yes | Esophageal muscularis; Lung; Skeletal muscle; Skin; Subcutaneous adipose; Tibial nerve; Transformed fibroblasts |
rs11606902 | PRSS23 | Yes | No | Adrenal gland; Esophagus; Skeletal muscle |
rs6095946 | PTPN1 | Yes | Yes | None |
rs10774624 | SH2B3 | Yes | No | Esophageal mucosa; Skin |
rs55892100 | TES | Yes | Yes | Adrenal gland; Lung; Pancreas; Subcutaneous adipose; Testis; Tibial artery; Tibial nerve; Thyroid; Whole blood |
Gene | Description | Fold Change | p |
---|---|---|---|
MCPH1 | Microcephalin 1 | 2.18 | 2.4 × 10−2 |
MAFB | MAF BZIP transcription factor B | −2.12 | 1.9 × 10−2 |
HGF | Hepatocyte growth factor | −2.52 | 3.1 × 10−2 |
PCSK5 | Proprotein convertase subtilisin/kexin type 5 | −2.75 | 3.2 × 10−2 |
lncRNA | Sequence Homology | Fold Change | p |
---|---|---|---|
NONHSAT157336.1:208–1549 | Myoferlin | 1.61 × 105 | 3.6 × 10−2 |
NONHSAT106523.2:1153–1748 | Forkhead box C1 | 2.26 × 103 | 4.5 × 10−2 |
NONHSAT184643.1:226–631 | Spectrin β, non-erythrocytic 1 | 4.77 | 1.6 × 10−2 |
NONHSAT156133.1:88–552 | Transcription factor 7 like 2 | −2.42 | 2.5 × 10−2 |
Donor | 17β-Estradiol Concentration | |
---|---|---|
Non-glaucomatous (n = 4) | 0.14 ± 0.05 nM | 37.90 ± 14.80 pg/mL |
Glaucomatous (n = 4) | 0.13 ± 0.03 nM | 34.46 ± 7.08 pg/mL |
Bovine (n = 5) | 0.22 ± 0.03 nM | 59.70 ± 8.58 pg/mL |
Porcine (n = 4) | 0.55 ± 0.62 nM | 149.44 ± 168.21 pg/mL |
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Youngblood, H.A.; Parker, E.; Cai, J.; Perkumas, K.; Yu, H.; Sun, J.; Smith, S.B.; Bollinger, K.E.; Wiggs, J.L.; Pasquale, L.R.; et al. Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes. Int. J. Mol. Sci. 2021, 22, 10288. https://doi.org/10.3390/ijms221910288
Youngblood HA, Parker E, Cai J, Perkumas K, Yu H, Sun J, Smith SB, Bollinger KE, Wiggs JL, Pasquale LR, et al. Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes. International Journal of Molecular Sciences. 2021; 22(19):10288. https://doi.org/10.3390/ijms221910288
Chicago/Turabian StyleYoungblood, Hannah A., Emily Parker, Jingwen Cai, Kristin Perkumas, Hongfang Yu, Jason Sun, Sylvia B. Smith, Kathryn E. Bollinger, Janey L. Wiggs, Louis R. Pasquale, and et al. 2021. "Identification of Estrogen Signaling in a Prioritization Study of Intraocular Pressure-Associated Genes" International Journal of Molecular Sciences 22, no. 19: 10288. https://doi.org/10.3390/ijms221910288