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Title

The Cis-Regulatory Architecture of Mammalian Photoreceptors

Date of Award

Summer 8-15-2012

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Crx is the principal transcription factor of the photoreceptor transcriptional network and is a key regulator of photoreceptor differentiation and survival. Mice mutant for Crx lack functional photoreceptors and are blind at birth. Mutations in human CRX are associated with several retinal diseases including autosomal dominant cone-rod dystrophy 2 and Leber's congenital amaurosis, a severe form of blindness in newborns. Given the importance of Crx in photoreceptor development and maintenance, genome-wide mapping of Crx binding sites was used to facilitate identification of photoreceptor cis-regulatory elements. ChIP-seq against Crx identified thousands of cis-regulatory regions around photoreceptor genes in adult mouse retina. Crx directly regulates downstream photoreceptor transcription factors and their target genes via a network of spatially distributed regulatory elements around each locus. Crx-bound regions act in a synergistic fashion to activate transcription and contain multiple Crx binding sites which interact in a spacing- and orientation-dependent manner to fine-tune transcript levels. Crx ChIP-seq was also performed on Nrl mutant retinas, which represent an enriched source of cone photoreceptors. Comparison with the wild-type ChIP-seq dataset identified numerous rod- and cone-specific Crx-bound regions as well as many shared elements. Thus, Crx combinatorially orchestrates the transcriptional networks of both rods and cones by coordinating the expression of photoreceptor genes including most retinal disease genes. This study pinpoints thousands of non-coding regions of relevance to both Mendelian and complex retinal disease and allows prioritization of human retinal disease genes which has already resulted in identification of FAM161A and MAK, novel disease genes implicated in retinitis pigmentosa.

Language

English (en)

Chair and Committee

Joseph Corbo

Committee Members

David Beebe, Shiming Chen, Aaron DiAntonio, Justin Fay, Vladimir Kefalov

Comments

Permanent URL: https://doi.org/10.7936/K79P2ZKW

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