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Joseph Corbo, Daniel Murphy, Andrew Hughes; Shared and divergent aspects of cis-regulatory architecture in photoreceptors and bipolar cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3065.
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Retinal photoreceptors and bipolar cells are considered “sister” cell types, sharing many similarities in gene expression and synaptic structure reflective of their common evolutionary origin from an ancestral photoreceptor-like cell. Whether the similarities between these two cell types extend to the level of cis-regulatory architecture is currently unknown.
Here, we use ATAC-seq and RNA-seq to profile the accessible chromatin landscape and gene expression patterns of bipolar cells and sub-populations of ON-, and OFF-bipolar cells from the adult mouse retina, comparing them to previously generated datasets from photoreceptors.
We identified regions of open chromatin and gene expression patterns that are shared and unique to each cell type. We found differences in open chromatin between photoreceptors and bipolars that correlated with differential gene expression. Fewer differences were found between ON- and OFF-bipolars. We also identified key differences in the patterns of transcription factor binding site enrichment in the cis-regulatory regions of photoreceptors and bipolar cells. Whereas both photoreceptor and bipolar cell cis-regulatory regions share an abundance of K50-type homeodomain binding sites, consistent with regulation by CRX and OTX2, only photoreceptor cell cis-regulatory regions contain Q50-homeodomain motifs. Since Q50 motifs are bound by the bipolar-specific transcriptional repressor, VSX2, we hypothesis that the presence of Q50 motifs in photoreceptor cis-regulatory regions serves to repress photoreceptor genes in bipolar cells.
We have defined the cis-regulatory architecture of adult mouse bipolar cells for the first time and compared it to that of photoreceptors. We discovered that these two sister cell types share many cis-regulatory features, most notably an abundance of K50 homeodomain binding sites in their cis-regulatory regions. This finding suggests that a K50 homeodomain, such as OTX2, was likely a key transcriptional regulator in the ancestral photoreceptor-like cell that gave rise to both cell types in the course of evolution. In addition, we hypothesize that Q50 motifs evolved in the cis-regulatory regions of photoreceptors as a means of driving the evolutionary divergence of these two cell types.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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