Identifying Signature Profiles of Transcription Factors in Human and Mouse Models of Retinal Disease

Abstract

Purpose : Transcription factors (TF) regulate a complex array of gene networks to orchestrate formation and maintenance of the mammalian retina. This study will be useful to understand the complex mechanisms that gives rise to a functional retina. The purpose of this work is to determine the expression signature profile of transcription factor genes in the developing and mature retina.

Methods : RNA samples were collected from the following tissues of C57Bl6/J mice for quantitative real time PCR: whole eye at embryonic time point (E) 10, 12, 14, 16, 18 and postnatal day (P) 2 and 6; mature rod and cone photoreceptor cells; aged retinal pigment epithelium (RPE); E18 and P30 retinas of rd7^-/-; and RORA cone, retinal progenitor, and RPE conditional mutants. Real time PCR was conducted in a total of 176 transcription factors. Approximately 130 of these transcription factors are expressed in humans. TF profiles were generated from RNAseq transcriptome analysis of RPE/choroid and retina from an AMD cohort of fresh donor eye tissue (n=30 individuals). TF expression profile was created based on the highest peak of expression. Factors were grouped in three main clusters: peak expression at a single time point, multiple peaks at different embryonic time points and multiple peaks of expression at embryonic and adult time points.

Results : The majority of transcription factors have a single peak expression during development and persistent expression in the adult retina. While a majority of transcription factors were not rod, cone, or RPE specific, this study identified several cell type specific TF. Common and specific transcription factor signature profiles were identified for each mutant model. A total of 82 factors including CRX, Nr2e3, RORA, RORB, and SAG, had highly significant differential expression in the AMD patient cohort.

Conclusions : This study examines the transcriptional signature of developing retinal cells and distinguishes which factors are further required in mature rod and cone photoreceptor cells as well as RPE. Additionally, we determine which of these transcription factors are affected in the retina or RPE of retinal disease models and in patients with age related macular degeneration. This study delineates the transcriptional signature profile of factors that modulate normal and pathogenic retinal function.

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