TY - JOUR
T1 - GLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans
AU - Nair, K. Saidas
AU - Srivastava, Chitrangda
AU - Brown, Robert V.
AU - Koli, Swanand
AU - Choquet, Hélène
AU - Kang, Hong Soon
AU - Kuo, Yien Ming
AU - Grimm, Sara A.
AU - Sutherland, Caleb
AU - Badea, Alexandra
AU - Johnson, G. Allan
AU - Zhao, Yin
AU - Yin, Jie
AU - Okamoto, Kyoko
AU - Clark, Graham
AU - Borrás, Terete
AU - Zode, Gulab
AU - Kizhatil, Krishnakumar
AU - Chakrabarti, Subhabrata
AU - John, Simon W.M.
AU - Jorgenson, Eric
AU - Jetten, Anton M.
N1 - Funding Information:
A.M.J. research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS), the National Institutes of Health (NIH) [Z01-ES-100485]. The authors thank Laura Miller-de Graff for her outstanding assistance with breeding the knockout mice. This work was supported in part by the National Eye Institute (NEI) grants R01 EY027004 (H.C. and E.J.) EY022891 (K.S.N.), EY028175 (K.K.), EY011721 (S.W.M.J.), EY026220 EY026177 (G.Z.), and EY12731291 (T.B.), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01 DK116738 (H.C. and E.J.), NEI P30 EY002162 core grant for vision research (UCSF, Ophthalmology), Research to Prevent Blindness unrestricted grant (UCSF Ophthalmology), and grants from That Man May See Inc., Brightfocus Foundation (G2019360), UCSF Academic Senate Committee on Research (RAP grant), Marin Community Foundation-Kathlyn Masneri and Arno Masneri Fund (K.S.N.). S.C. is supported by a grant from the Department of Biotechnology, Government of India grant (BT/PR32404/MED/30/2136/2019). S.W.M.J. is an HHMI investigator and received funding from the Precision Medicine Initiative at Columbia University.
Publisher Copyright:
© 2021, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85112693477&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25181-7
DO - 10.1038/s41467-021-25181-7
M3 - Article
C2 - 34385434
AN - SCOPUS:85112693477
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4877
ER -