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

• Published in: Nature communications Vol. 7; no. 1; p. 10953
• Main Authors: Khan, Shahid Y., Vasanth, Shivakumar, Kabir, Firoz, Gottsch, John D., Khan, Arif O., Chaerkady, Raghothama, Lee, Mei-Chong W., Leitch, Carmen C., Ma, Zhiwei, Laux, Julie, Villasmil, Rafael, Khan, Shaheen N., Riazuddin, Sheikh, Akram, Javed, Cole, Robert N., Talbot, C. Conover, Pourmand, Nader, Zaghloul, Norann A., Hejtmancik, J. Fielding, Riazuddin, S. Amer
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.04.2016; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 631/208/2489/144; 631/337/572; 631/45/612/1981; 692/699/3161; 82/81; Animals; Autophagy; Autophagy - genetics; Chromosomes; Corneal Opacity - genetics; Corneal Opacity - metabolism; Disease; Epithelial Cells - metabolism; Epithelial Cells - pathology; Eye Abnormalities - genetics; Eye Abnormalities - metabolism; Family Health; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Knockdown Techniques; Genomes; Genotype & phenotype; HEK293 Cells; HSP40 Heat-Shock Proteins - genetics; HSP40 Heat-Shock Proteins - metabolism; Humanities and Social Sciences; Humans; Lens, Crystalline - pathology; Male; Medicine; multidisciplinary; Mutation; Pedigree; Proteins; Science; Science (multidisciplinary); Transcription factors; Whole Exome Sequencing - methods; Zebrafish - genetics; Zebrafish - metabolism; Lahore Pakistan; Pakistan; California; United States > US; Maryland; Baltimore Maryland
• DOI: 10.1038/ncomms10953
• ISSN: 2041-1723

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. Peter's Anomaly is a developmental disorder of the eye and has been linked to mutations in a range of genes, including the transcription factor FOXE3. Here the authors use next-generation RNA sequencing and mass spectrometry to identify an autophagy-associated protein, DNAJB1 as the transcriptional target of FOXE3.