Transcriptome-based insights into gene networks controlling myopia prevention.

Abstract

Myopia (short-sightedness), usually caused by excessive elongation of the eye during development, has reached epidemic proportions worldwide. In animal systems including the chicken model, several treatments have been shown to inhibit ocular elongation and experimental myopia. Although diverse in their apparent mechanism of action, each one leads to a reduction in the rate of ocular growth. We hypothesize that a defined set of retinal molecular changes may underlie growth inhibition, irrespective of the treatment agent used. Accordingly, across five well-established but diverse methods of inhibiting myopia, significant overlap is seen in the retinal transcriptome profile (transcript levels and alternative splicing events) in chicks when analyzed by RNA-seq. Within the two major pathway networks enriched during growth inhibition, that of cell signaling and circadian entrainment, transcription factors form the largest functional grouping. Importantly, a large percentage of those genes forming the defined retinal response are downstream targets of the transcription factor EGR1 which itself shows a universal response to all five growth-inhibitory treatments. This supports EGR1's previously implicated role in ocular growth regulation. Finally, by contrasting our data with human linkage and GWAS studies on refractive error, we confirm the applicability of our study to the human condition. Together, these findings suggest that a universal set of transcriptome changes, which sit within a well-defined retinal network that cannot be bypassed, is fundamental to growth regulation, thus paving a way for designing novel targets for myopia therapies.

• Authors: Cindy Karouta, Robert Kucharski, Kristine Hardy, Kate Thomson, Ryszard Maleszka, Ian Morgan, Regan Ashby
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 9 Pg. e21846 (09 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 34405458 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid
• Early Growth Response Protein 1
• Phosphinic Acids
• Pyridines
• STAT Transcription Factors
• Tetrahydronaphthalenes
• Pirenzepine
• ADTN
• Atropine
• Janus Kinases

Topics

• Alternative Splicing (drug effects)
• Animals
• Atropine (pharmacology)
• Chickens
• Circadian Rhythm (drug effects)
• Early Growth Response Protein 1 (metabolism)
• Eye (drug effects, growth & development, metabolism)
• Gene Expression Regulation (drug effects)
• Gene Regulatory Networks (drug effects)
• Humans
• Janus Kinases (metabolism)
• Male
• Models, Biological
• Myopia (genetics, prevention & control)
• Phosphinic Acids (pharmacology)
• Pirenzepine (pharmacology)
• Pyridines (pharmacology)
• Reproducibility of Results
• Retina (drug effects, growth & development, metabolism)
• STAT Transcription Factors (metabolism)
• Tetrahydronaphthalenes (pharmacology)
• Time Factors
• Transcriptome (drug effects)