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GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans

Author

Listed:
  • K. Saidas Nair

    (University of California, San Francisco)

  • Chitrangda Srivastava

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Robert V. Brown

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Swanand Koli

    (University of California, San Francisco)

  • Hélène Choquet

    (Kaiser Permanente Northern California, Division of Research)

  • Hong Soon Kang

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Yien-Ming Kuo

    (University of California, San Francisco)

  • Sara A. Grimm

    (Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Caleb Sutherland

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Alexandra Badea

    (Duke University)

  • G. Allan Johnson

    (Duke University)

  • Yin Zhao

    (University of California, San Francisco)

  • Jie Yin

    (Kaiser Permanente Northern California, Division of Research)

  • Kyoko Okamoto

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

  • Graham Clark

    (The Jackson Laboratory)

  • Terete Borrás

    (University of North Carolina School of Medicine)

  • Gulab Zode

    (University of North Texas Health Science Center)

  • Krishnakumar Kizhatil

    (The Jackson Laboratory)

  • Subhabrata Chakrabarti

    (Brien Holden Eye Research Centre, L. V. Prasad Eye Institute)

  • Simon W. M. John

    (The Jackson Laboratory
    Columbia University)

  • Eric Jorgenson

    (Regeneron Pharmaceuticals, Inc)

  • Anton M. Jetten

    (Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health)

Abstract

Chronically elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. Dysfunction of the trabecular meshwork (TM), which controls the outflow of aqueous humor (AqH) from the anterior chamber, is the major cause of elevated IOP. Here, we demonstrate that mice deficient in the Krüppel-like zinc finger transcriptional factor GLI-similar-1 (GLIS1) develop chronically elevated IOP. Magnetic resonance imaging and histopathological analysis reveal that deficiency in GLIS1 expression induces progressive degeneration of the TM, leading to inefficient AqH drainage from the anterior chamber and elevated IOP. Transcriptome and cistrome analyses identified several glaucoma- and extracellular matrix-associated genes as direct transcriptional targets of GLIS1. We also identified a significant association between GLIS1 variant rs941125 and glaucoma in humans (P = 4.73 × 10−6), further supporting a role for GLIS1 into glaucoma etiology. Our study identifies GLIS1 as a critical regulator of TM function and maintenance, AqH dynamics, and IOP.

Suggested Citation

  • K. Saidas Nair & Chitrangda Srivastava & Robert V. Brown & Swanand Koli & Hélène Choquet & Hong Soon Kang & Yien-Ming Kuo & Sara A. Grimm & Caleb Sutherland & Alexandra Badea & G. Allan Johnson & Yin , 2021. "GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25181-7
    DOI: 10.1038/s41467-021-25181-7
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