2. Academic Validation
  3. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1

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

  • Nat Commun. 2016 Apr 6;7:10953. doi: 10.1038/ncomms10953.
Shahid Y Khan 1,  Shivakumar Vasanth 1,  Firoz Kabir 1,  John D Gottsch 1,  Arif O Khan 2,  Raghothama Chaerkady 3,  Mei-Chong W Lee 4,  Carmen C Leitch 5,  Zhiwei Ma 6,  Julie Laux 7,  Rafael Villasmil 7,  Shaheen N Khan 8,  Sheikh Riazuddin 8 9 10,  Javed Akram 9 10,  Robert N Cole 3,  C Conover Talbot 11,  Nader Pourmand 4,  Norann A Zaghloul 5,  J Fielding Hejtmancik 6,  S Amer Riazuddin 1
Affiliations

Affiliations

  • 1 The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
  • 2 King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia.
  • 3 Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
  • 4 Department of Biomolecular Engineering, University of California, Santa Cruz, California 94305, USA.
  • 5 Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201, USA.
  • 6 Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 7 Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 8 National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
  • 9 Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.
  • 10 National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
  • 11 Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
PMID: 27218149 DOI: 10.1038/ncomms10953
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.

Figures