Investigation of Tdrd7-based regulation in the ocular lens by integrated multiomics approach
Date
2020
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Publisher
University of Delaware
Abstract
Clouding of the eye lens, termed cataract, is the leading cause of blindness worldwide. Mutations in Tdrd7 (Tudor domain containing protein 7) causes congenital cataract in human and mouse. Tdrd7 protein is an RNA granule component that is involved in several aspects of post-transcriptional regulation. Tdrd7 protein is predicted to participate in protein-protein interactions via its Tudor domains and OST-HTH/LOTUS domains. MicroRNAs (miRNAs), a class of small noncoding RNAs, are also known to regulate gene expression post-transcriptionally and have been implicated in the pathogenesis of cataract. However, the impact of Tdrd7 deficiency on miRNAs in the lens is unexplored. In this study, we used Tdrd7-targeted germline knockout (Tdrd7-/-) mouse, which exhibit fully penetrant cataract, as a model to investigate the impact of Tdrd7 on miRNAs. We performed RNA-seq to analyze small RNA expression in postnatal day 15 Tdrd7-/- mouse lens. Differential expression analysis identified significantly mis-expressed miRNAs in Tdrd7-/- mouse lens prior to the detection of overt cataract suggesting their potential involvement in gene expression control. Using a multiomics integrated approach, the analysis of these differentially expressed miRNAs in the context of genome-wide mRNA expression profiling data and proteome data on Tdrd7-/- mouse lenses informs on the regulatory network underlying lens defects resulting from Tdrd7 deficiency. In sum, this work identifies miRNAs downstream of Tdrd7, and predicts their potential targets, in turn providing new evidence that supports a role for post-transcriptional regulatory factors in lens development and early-onset cataractogenesis.
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Keywords
Cataracts, Blindness, Tdrd7