TET-dependent GDF7 hypomethylation impairs aqueous humor outflow and serves as a potential therapeutic target in glaucoma.

Abstract

Glaucoma is the leading cause of irreversible vision loss, affecting more than 70 million individuals worldwide. Circulatory disturbances of aqueous humor (AH) have long been central pathological contributors to glaucomatous lesions. Thus, targeting the AH outflow is a promising approach to treat glaucoma. However, the epigenetic mechanisms initiating AH outflow disorders and the targeted treatments remain to be developed. Studying glaucoma patients, we identified GDF7 (growth differentiation factor 7) hypomethylation as a crucial event in the onset of AH outflow disorders. Regarding the underlying mechanism, the hypomethylated GDF7 promoter was responsible for the increased GDF7 production and secretion in primary open-angle glaucoma (POAG). Excessive GDF7 protein promoted trabecular meshwork (TM) fibrosis through bone morphogenetic protein receptor type 2 (BMPR2)/Smad signaling and upregulated pro-fibrotic genes, α-smooth muscle actin (α-SMA) and fibronectin (FN). GDF7 protein expression formed a positive feedback loop in glaucomatous TM (GTM). This positive feedback loop was dependent on the activated TET (ten-eleven translocation) enzyme, which kept the GDF7 promoter region hypomethylated. The phenotypic transition in TM fortified the AH outflow resistance, thus elevating the intraocular pressure (IOP) and attenuating the nerve fiber layer. This methylation-dependent mechanism is also confirmed by a machine-learning model in silico with a specificity of 84.38% and a sensitivity of 89.38%. In rhesus monkeys, we developed GDF7 neutralization therapy to inhibit TM fibrosis and consequent AH outflow resistance that contributes to glaucoma. The neutralization therapy achieved high-efficiency control of the IOP (from 21.3 ± 0.3 to 17.6 ± 0.2 mmHg), a three-fold improvement in the outflow facility (from 0.1 to 0.3 μL/min · mmHg), and protection of nerve fibers. This study provides new insights into the epigenetic mechanism of glaucoma and proposes an innovative GDF7 neutralization therapy as a promising intervention.

• Authors: Peixing Wan, Erping Long, Zhidong Li, Yingting Zhu, Wenru Su, Yehong Zhuo
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 4 Pg. 1639-1657 (04 07 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 33388417 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• ACTA2 protein, human
• Actins
• Bone Morphogenetic Proteins
• GDF7 protein, human
• Growth Differentiation Factors
• Proto-Oncogene Proteins
• Smad Proteins
• Mixed Function Oxygenases
• TET1 protein, human
• BMPR2 protein, human
• Bone Morphogenetic Protein Receptors, Type II

Topics

• Actins (genetics)
• Animals
• Aqueous Humor (metabolism)
• Bone Morphogenetic Protein Receptors, Type II (genetics)
• Bone Morphogenetic Proteins (antagonists & inhibitors, genetics)
• DNA Methylation (genetics)
• Disease Models, Animal
• Fibrosis (genetics, pathology, therapy)
• Glaucoma, Open-Angle (genetics, pathology, therapy)
• Growth Differentiation Factors (antagonists & inhibitors, genetics)
• Humans
• Macaca mulatta (genetics)
• Mixed Function Oxygenases (genetics)
• Proto-Oncogene Proteins (genetics)
• Signal Transduction (genetics)
• Smad Proteins (genetics)
• Trabecular Meshwork (metabolism, pathology)