TY - JOUR
T1 - Identification of estrogen signaling in a prioritization study of intraocular pressure-associated genes
AU - Youngblood, Hannah A.
AU - Parker, Emily
AU - Cai, Jingwen
AU - Perkumas, Kristin
AU - Yu, Hongfang
AU - Sun, Jason
AU - Smith, Sylvia B.
AU - Bollinger, Kathryn E.
AU - Wiggs, Janey L.
AU - Pasquale, Louis R.
AU - Hauser, Michael A.
AU - Stamer, W. Daniel
AU - Liu, Yutao
N1 - Funding Information:
Acknowledgments: The authors thank all of the donors for their ocular samples. This study would not be feasible without these precious samples. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 12/3/2018. Parts of this manuscript were presented at the 2020 ARVO Annual Meeting by Yutao Liu and the 2021 ARVO Annual Meeting by Hannah A. Youngblood.
Funding Information:
Funding: This research was funded by the BrightFocus Foundation; Fight for Sight; The Glaucoma Foundation; the Glaucoma Research Foundation; Research to Prevent Blindness; and the National Institutes of Health, F31EY031973, P30EY005722, P30EY031631, R01EY023242, R01EY022359, R01EY023287, R01EY015473, R01EY032559, and R21EY028671. The APC was funded by R01EY023242.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with ESR1 mediating 25 interactions. Several genes (i.e., EFEMP1, FOXC1, and SPTBN1) regulated by β-estradiol/ESR1 were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm’s canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed ESR1 gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.
AB - Elevated intraocular pressure (IOP) is the only modifiable risk factor for primary open-angle glaucoma (POAG). Herein we sought to prioritize a set of previously identified IOP-associated genes using novel and previously published datasets. We identified several genes for future study, including several involved in cytoskeletal/extracellular matrix reorganization, cell adhesion, angiogenesis, and TGF-β signaling. Our differential correlation analysis of IOP-associated genes identified 295 pairs of 201 genes with differential correlation. Pathway analysis identified β-estradiol as the top upstream regulator of these genes with ESR1 mediating 25 interactions. Several genes (i.e., EFEMP1, FOXC1, and SPTBN1) regulated by β-estradiol/ESR1 were highly expressed in non-glaucomatous human trabecular meshwork (TM) or Schlemm’s canal (SC) cells and specifically expressed in TM/SC cell clusters defined by single-cell RNA-sequencing. We confirmed ESR1 gene and protein expression in human TM cells and TM/SC tissue with quantitative real-time PCR and immunofluorescence, respectively. 17β-estradiol was identified in bovine, porcine, and human aqueous humor (AH) using ELISA. In conclusion, we have identified estrogen receptor signaling as a key modulator of several IOP-associated genes. The expression of ESR1 and these IOP-associated genes in TM/SC tissue and the presence of 17β-estradiol in AH supports a role for estrogen signaling in IOP regulation.
KW - Aqueous humor outflow
KW - Estrogen signaling
KW - Intraocular pressure
KW - Primary open-angle glaucoma
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U2 - 10.3390/ijms221910288
DO - 10.3390/ijms221910288
M3 - Article
C2 - 34638643
AN - SCOPUS:85115612418
SN - 1422-0067
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 19
M1 - 10288
ER -