title: FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1.
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.
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: Shahid Y
authors.initials: SY
authors.lastname: Khan
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: Shivakumar
authors.initials: S
authors.lastname: Vasanth
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: Firoz
authors.initials: F
authors.lastname: Kabir
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
authors.affiliation: King Khaled Eye Specialist Hospital, Riyadh 11462, Saudi Arabia.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
authors.forename: Raghothama
authors.initials: R
authors.lastname: Chaerkady
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, California 94305, USA.
authors.forename: Mei-Chong W
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201, USA.
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Leitch
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Laux
authors.affiliation: Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Villasmil
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.
authors.forename: Shaheen N
authors.initials: SN
authors.lastname: Khan
authors.affiliation: National Centre of Excellence in Molecular Biology, University of the Punjab, Lahore 53700, Pakistan.|Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.|National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.affiliation: Allama Iqbal Medical College, University of Health Sciences, Lahore 54550, Pakistan.|National Centre for Genetic Diseases, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad 44000, Pakistan.
authors.forename: Javed
authors.initials: J
authors.lastname: Akram
authors.affiliation: Department of Biological Chemistry, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.affiliation: Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, Maryland 21205, USA.
authors.forename: C Conover
authors.initials: CC
authors.lastname: Talbot
authors.affiliation: Department of Biomolecular Engineering, University of California, Santa Cruz, California 94305, USA.
authors.forename: Nader
authors.initials: N
authors.lastname: Pourmand
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, 660 West Redwood Street, Baltimore, Maryland 21201, USA.
authors.forename: Norann A
authors.initials: NA
authors.lastname: Zaghloul
authors.affiliation: Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: J Fielding
authors.initials: JF
authors.lastname: Hejtmancik
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics*; D003318:Corneal Opacity / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007908:Lens, Crystalline / Q000473:pathology; D008297:Male; D010375:Pedigree; D000073359:Exome Sequencing / Q000379:methods; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: C494647:DNAJB1 protein, human; C404285:FOXE3 protein, human; D051858:Forkhead Transcription Factors; D050956:HSP40 Heat-Shock Proteins