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Published on: June 15, 2017
A distant, cis-acting enhancer drives induction of Arf by Tgfβ in the developing eye
Yanbin Zheng1, Caitlin Devitt, Jing Liu
1Division of Hematology-Oncology, Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd. MC 9063, Dallas, TX 75390, USA.
Abstract:
The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development: its gene product, p19(Arf), is induced by Tgfβ2 in the developing eye to dampen proliferative signals from Pdgfrβ, which effect ultimately fosters the vascular remodeling required for normal vision in the mouse. Mechanisms underlying Arf induction by Tgfβ2 are not fully understood. Using the chr4(Δ70 kb/Δ70 kb) mouse, we now show that deletion of the coronary artery disease (CAD) risk interval lying upstream of the Cdkn2a/b locus represses developmentally-timed induction of Arf resulting in eye disease mimicking the persistent hyperplastic primary vitreous (PHPV) found in Arf-null mice and in children. Using mouse embryo fibroblasts, we demonstrate that Arf induction by Tgfβ is blocked in cis to the 70 kb deletion, but Arf induction by activated RAS and cell culture "shock" is not. Finally, we show that Arf induction by Tgfβ is derailed by preventing RNA polymerase II recruitment following Smad 2/3 binding to the promoter. These findings provide the first evidence that the CAD risk interval, located at a distance from Arf, acts as a cis enhancer of Tgfβ2-driven induction of Arf during development.
Insights
A coronary artery disease risk interval regulates Arf gene induction crucial for eye development. Deleting this interval causes eye disease by blocking Tgfβ2-driven Arf expression.
Area of Science:
- Genetics
- Developmental Biology
- Ophthalmology
Background:
- The Arf tumor suppressor is vital for preventing cancer and normal eye development.
- Arf (p19Arf) is induced by Tgfβ2 in the developing eye to regulate vascular remodeling for vision.
- Mechanisms of Arf induction by Tgfβ2 are not fully understood.
Purpose of the Study:
- To investigate the role of a coronary artery disease (CAD) risk interval upstream of the Cdkn2a/b locus in Arf gene regulation during eye development.
- To elucidate the cis-regulatory mechanisms underlying Tgfβ2-induced Arf expression.
Main Methods:
- Utilized a chr4(Δ70 kb/Δ70 kb) mouse model with a deletion in the CAD risk interval.
- Employed mouse embryo fibroblasts to study Arf induction by Tgfβ, activated RAS, and cell culture shock.
- Investigated RNA polymerase II recruitment and Smad 2/3 binding to the Arf promoter.
Main Results:
- Deletion of the CAD risk interval repressed developmentally-timed Arf induction, leading to eye disease resembling persistent hyperplastic primary vitreous (PHPV).
- Arf induction by Tgfβ was blocked in cis to the 70 kb deletion, but not by RAS activation or cell shock.
- Tgfβ-induced Arf expression was impaired by preventing RNA polymerase II recruitment after Smad 2/3 binding.
Conclusions:
- The CAD risk interval functions as a cis-enhancer of Tgfβ2-driven Arf induction during eye development.
- This study reveals a novel regulatory mechanism linking a genetic risk factor for CAD to developmental processes in the eye.
- Findings provide insights into the pathogenesis of PHPV and potential therapeutic targets.
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