FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

Shahid Y. Khan, Shivakumar Vasanth, Firoz Kabir, John D. Gottsch, Arif O. Khan, Raghothama Chaerkady, Mei-Chong W. Lee, Carmen C. Leitch, Zhiwei Ma, Julie Laux, Rafael Villasmil, Shaheen N. Khan, Sheikh Riazuddin, Javed Akram, Robert N. Cole, C. Conover Talbot, Nader Pourmand, Norann A. Zaghloul, J. Fielding Hejtmancik and S. Amer Riazuddin ()
Additional contact information
Shahid Y. Khan: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
Shivakumar Vasanth: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
Firoz Kabir: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
John D. Gottsch: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA
Arif O. Khan: King Khaled Eye Specialist Hospital
Raghothama Chaerkady: Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA
Mei-Chong W. Lee: University of California
Carmen C. Leitch: Diabetes, and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201, USA
Zhiwei Ma: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health
Julie Laux: Laboratory of Immunology, National Eye Institute, National Institutes of Health
Rafael Villasmil: Laboratory of Immunology, National Eye Institute, National Institutes of Health
Shaheen N. Khan: National Centre of Excellence in Molecular Biology, University of the Punjab
Sheikh Riazuddin: National Centre of Excellence in Molecular Biology, University of the Punjab
Javed Akram: Allama Iqbal Medical College, University of Health Sciences
Robert N. Cole: Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA
C. Conover Talbot: Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA
Nader Pourmand: University of California
Norann A. Zaghloul: Diabetes, and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201, USA
J. Fielding Hejtmancik: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health
S. Amer Riazuddin: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract FOXE3 is a lens-specific transcription factor that has been associated with anterior segment ocular dysgenesis. To determine the transcriptional target(s) of FOXE3 that are indispensable for the anterior segment development, we examined the transcriptome and the proteome of cells expressing truncated FOXE3 responsible for Peters anomaly identified through linkage-coupled next-generation whole-exome sequencing. We found that DNAJB1, an autophagy-associated protein, was the only candidate exhibiting differential expression in both screens. We confirmed the candidacy of DNAJB1 through chromatin immunoprecipitation and luciferase assays while knockdown of DNAJB1 in human lens epithelial cells resulted in a mitotic arrest. Subsequently, we targeted dnajb1a in zebrafish through injection of a splice-blocking morpholino. The dnajb1a morphants exhibited underdeveloped cataractous lenses with persistent apoptotic nuclei. In conclusion, here we report DNAJB1 is a transcriptional target of FOXE3 in a novel pathway that is crucial for the development of the anterior segment of the eye.

Date: 2016
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DOI: 10.1038/ncomms10953

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