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

K Saidas Nair,Hélène Choquet,Robert V Brown,Terete Borrás,Hong Soon Kang,Jie Yin,Caleb Sutherland,Sara A Grimm,Yien–Ming Kuo ,Eric Jorgenson,Zhang Yin ,Gulab Zode,Kazushi Okamoto ,Chitrangda Srivastava,Graham Clark,Subhabrata Chakrabarti,Simon W M John,Swanand Koli,Krishnakumar Kizhatil,Alexandra Badea,G Allan Johnson,Anton M Jetten

doi:10.1038/s41467-021-25181-7

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.

Highlights

Elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness
These data indicate that loss of the zinc finger (ZF) and transactivation domain (TAD) in Glis1-KO mice abolishes the ability of GLIS1 to recognize the GLIS binding site (GLISBS) and to regulate the transcription of target genes
Because protruding eyes are well-established comorbidity commonly associated with Graves’ disease, an autoimmune disease leading to hyperthyroidism[31], and since GLIS1 and GLIS3 family members have been implicated in several thyroid glandassociated diseases[25,27,32,33], we examined whether this Glis1KO phenotype was related to the development of Graves’ disease that is characterized by high circulating levels of T3/T4 and low TSH

Summary

Introduction

Elevated intraocular pressure (IOP) is the major risk factor of primary open-angle glaucoma, a leading cause of blindness. 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. We examine the function of GLIS1 in ocular tissues in more detail and demonstrate that GLIS1 plays a critical regulatory role in maintaining normal TM structure and IOP. We have detected significant associations between common genetic variants in the GLIS1 region and POAG in humans, thereby supporting the role of GLIS1 as a glaucoma risk gene. These variants may impact TM functions and compromise AqH drainage thereby contributing to elevated IOP and glaucoma

Methods

Results

Conclusion