Identification of estrogen signaling in a prioritization study of intraocular pressure-associated genes

Hannah A. Youngblood, Emily Parker, Jingwen Cai, Kristin Perkumas, Hongfang Yu, Jason Sun, Sylvia B Smith, Kathryn E. Bollinger, Janey L. Wiggs, Louis R. Pasquale, Michael A. Hauser, W. Daniel Stamer, Yutao Liu

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article number10288
JournalInternational journal of molecular sciences
Volume22
Issue number19
DOIs
StatePublished - Oct 1 2021

Keywords

  • Aqueous humor outflow
  • Estrogen signaling
  • Intraocular pressure
  • Primary open-angle glaucoma

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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