September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Alternative splicing in the retina in a large family of genes is regulated by a single trans locus
Author Affiliations & Notes
  • J M Nickerson
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Felix L Struebing
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Shanu Markand
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Kevin Donaldson
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Salma Ferdous
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Jeffrey H Boatright
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Eldon E Geisert
    Ophthalmology, Emory Univeristy, Atlanta, Georgia, United States
  • Footnotes
    Commercial Relationships   J Nickerson, None; Felix Struebing, None; Shanu Markand, None; Kevin Donaldson, None; Salma Ferdous, None; Jeffrey Boatright, None; Eldon Geisert, None
  • Footnotes
    Support  NIH R01EY016470, R01EY021592, P30EY006360, R01EY014026, R01EY017841, DoD CDMRP Grant W81XWH1210255, Research to Prevent Blindness, the Katz Foundation.
Investigative Ophthalmology & Visual Science September 2016, Vol.57, No Pagination Specified. doi:
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      J M Nickerson, Felix L Struebing, Shanu Markand, Kevin Donaldson, Salma Ferdous, Jeffrey H Boatright, Eldon E Geisert; Alternative splicing in the retina in a large family of genes is regulated by a single trans locus. Invest. Ophthalmol. Vis. Sci. 201657(12):.

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      © 2017 Association for Research in Vision and Ophthalmology.

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Abstract

Purpose : Initial observation identified a potentially novel form of gene regulation. The first exons in some genes are highly expressed in retinas of the C57BL/6J mouse, but expressed minimally in the retinas of the DBA/2J mouse, suggesting the use of alternative transcription start sites in both strains. This study tests the hypothesis that a distant single gene locus regulates this differential expression of these numerous alternative splicing events.

Methods : We examined retinas from 55 BXD lines by Affymetrix ST2.0 microarrays to find each exon expressed highly in one but not the other strain (C57BL/6J and DBA/2J). Highly variant exons with a Linkage Related Score (LRS) >50 (p <1.0 x 10-5) were used to identify trans quantitative trait loci (QTLs) that may modulate differential expression. Criteria used in candidate gene analysis within the trans-QTL included: retina expression, nuclear location, involvement with transcription or splicing mechanisms, and a sequence variation that would be causative.

Results : 177 exons were differentially expressed with an LRS > 50. Many of those were first exons, suggesting alternative transcription start sites. A predominant locus found on chromosome 4 modulated the differential expression of 98 of these 177 exons. This locus contains 21 intergenic sites and 41 genes with non-synonymous SNPs, any one of which might control alternative splicing in our group of genes. In this chromosome 4 locus, Znf593 appeared to be the best candidate. Znf593 mRNA was detected at high levels in the retina (16 fold above mean mRNA expression level), it had a strong cis-QTL (LRS = 77), and it contained a non-synonymous proline to arginine change at amino acid 47. Immunoreactivity for Znf593 protein was found abundantly in nuclei of the GCL and to a lesser extent in the INL and ONL in both C57BL/6J and DBA/2J mouse eyes.

Conclusions : A single amino acid change (proline to arginine) in Znf593 may control differential splicing for a large family of retinally-expressed genes. Znf593, a C2H2-type Zinc finger protein, interacts with Oct transcription factors, which together might modulate differential splicing or alternative transcription start sites observed between the C57BL/6J and DBA/2J retinas.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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