Activating Transcription Factor 6 (ATF6): A Key Driver of Cataract-Associated Fibrosis

Cataracts, characterized by clouding of the eye's natural lens, are the second leading cause of blindness worldwide. Despite the availability of intraocular lens replacement surgery, there are currently no effective pharmacological treatments, highlighting the urgent need for new therapeutic strategies. The epithelial-mesenchymal transition (EMT) has been identified as the key factor of secondary cataract progression; however, the underlying mechanisms of EMT in lens epithelial cells remain unclear.

This research, published in the Genes & Diseases journal by a team from Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology, Capital Medical University and Shandong University elucidates the molecular mechanisms by which lens epithelial cells differentiate and contribute to secondary cataract formation.

Utilizing single-cell RNA sequencing (scRNA-seq) analysis, the researchers performed an extensive investigation of lens cells from fetuses aged 9 to 23 weeks. They unveiled the existence of two additional cell populations, distinct from the epithelial cells and fibers of the lens, namely transitional cells and “other cells”. Key markers such as FOXE3, SLC7A8, and SPARCL1 were highly expressed in lens epithelial cells—marking the first recognition of SPARCL1’s potential role in lens biology.

Furthermore, an integrative analysis of accessible-chromatin sequencing (scATAC-seq) and scRNA-seq data revealed the transcription factor ATF6 as a pivotal regulator of lens epithelial cell homeostasis. Notably, the active isoform, ATF6α, was highly expressed in epithelial cell clusters and was predicted to target 312 genes involved in cell cycle regulation and lens development, including PAX2 and MAF. These findings suggest a key role for ATF6α in the transcriptional regulation within lens epithelial cells.

Subsequent in vitro experiments demonstrated that ATF6 promotes EMT in lens epithelial cells, and antagonizing ATF6 effectively ameliorated epithelial interstitial fibrosis. Integrated transcriptomic and epigenomic analysis identified STAT3 as a downstream effector of ATF6. Additionally, western blot data confirmed that inhibition of ATF6 using Ceapin-A7 led to reduced phosphorylation of STAT3, suggesting a link between ATF6 activation and fibrotic changes associated with EMT.

Although the current study highlights the critical effect of ATF6 in epithelial cells, its role in animal models is yet to be explored. Nevertheless, the study demonstrates that ATF6 is significantly up-regulated in cellular models of cataract disease and its inhibition can effectively alleviate the EMT process in lens epithelial cells. In conclusion, this research provides a detailed single-cell atlas of lens epithelial cell development and identifies ATF6 as a potential therapeutic target.

Reference

Title of Original Paper: Integrated analysis of single-cell RNA-seq and ATAC-seq in lens epithelial cells: Unveiling the role of ATF6 as a key transcription factor

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101610

Funding Information:

The National Natural Science Foundation Project of China (No. 82271078)
Youth Beijing Scholar (No.076)
Beijing Municipal Public Welfare Development and Reform Pilot Project for Medical Research Institutes (No. PWD&RPP-MRI, JYY2023-6)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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(A) Schematic diagram of the human embryonic eyes design. (B) The uniform manifold approximation and projection (UMAP) algorithm was used to group the fetal lens scRNA-seq data into four clusters, each representing a unique combination of cell type and age. (C) UMAP embedding of the fetal lens scRNA-seq dataset, with individual cells colored by cell cycle. (D) The distribution of cell cycles in each cluster. (E) Within each fetal lens cluster, the top 10 most significant differences were observed in four distinct groups, namely lens fiber cells (FiberCell), transitional cells (TransitionalCell), lens epithelial cells (EpithelialCell), and unknown cluster (Others). (F) Marker gene expression distribution in lens epithelial cells and lens fiber cells.
(A) Heatmap of top 45 highly variable transcription factor activities among the three severity groups. The z-scores of transcription factor activities are color-coded. (B) Predicted transcription factors were explored through gene ontology (GO) and Reactome databases for functional enrichment analysis using Metascape. (C) The expression distribution of ATF6 in each cluster. ATF6, activating transcription factor 6.
(A) ATF6 binding schematic diagram, based on assays for ATAC-seq and using ATF6 motif for target gene prediction (BioRender: https://app.biorender.com). (B) Functional enrichment analysis for ATF6 target genes through gene ontology (GO) and Reactome databases. (C) STAT3 was the only gene located within 500 bp of the ATF6 promoter region. ATF6 promoter region TSS 500 gene overlays eye development pathways. (D) The protein level and quantification of STAT3 and p-STAT3 in primary lens epithelial cells treated with DMSO or Ceapin-A7 (n = 3/group; mean ± standard deviation; **P < 0.01; unpaired student's t-test). (E) The protein level and quantitative chart of STAT3 and p-STAT3 in TGF-β1 mediated primary lens epithelial cells treated with DMSO or Ceapin-A7 (n = 3/group; mean ± standard deviation; **P < 0.01; unpaired student's t-test). ATF6, activating transcription factor 6; TGF-β1, transforming growth factor beta 1; STAT3, signal transducer and activator of transcription 3; p-STAT3, phosphorylated STAT3.

18.07.2025 Compuscript Ltd

Regions: Asia, China, Europe, Ireland

Keywords: Science, Life Sciences

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