Abstract
Rod photoreceptors are specialized neurons that mediate vision in dim light and are the predominant photoreceptor type in nocturnal mammals. The rods of nocturnal mammals are unique among vertebrate cell types in having an ‘inverted’ nuclear architecture, with a dense mass of heterochromatin in the center of the nucleus rather than dispersed clumps at the periphery. To test if this unique nuclear architecture is correlated with a unique epigenomic landscape, we performed ATAC-seq on mouse rods and their most closely related cell type, cone photoreceptors. We find that thousands of loci are selectively closed in rods relative to cones as well as >60 additional cell types. Furthermore, we find that the open chromatin profile of photoreceptors lacking the rod master regulator Nrl is nearly indistinguishable from that of native cones, indicating that Nrl is required for selective chromatin closure in rods. Finally, we identified distinct enrichments of transcription factor binding sites in rods and cones, revealing key differences in the cis-regulatory grammar of these cell types. Taken together, these data provide insight into the development and maintenance of photoreceptor identity, and highlight rods as an attractive system for studying the relationship between nuclear organization and local changes in gene regulation.
Highlights
Emerging evidence indicates that the three-dimensional organization of chromatin within the nucleus is essential for regulating gene expression[5,6]
Through comparative analysis of these datasets, we define thousands of photoreceptor class- and subtype-specific candidate CREs, and we find that distinct subsets of these elements are enriched for different sets of transcription factor binding sites (TFBSs)
While we observed robust cell type-specific ATAC-seq peaks flanking known rod- and cone-specific genes, we noted that even highly cell type-specific loci frequently harbored peaks open in all three photoreceptor types (Supplementary Fig. S2). This multiplicity of both cell type-specific and shared open chromatin elements in photoreceptors is similar to the ‘locus complexity’ of cell type-specific enhancers recently described by Gonzalez et al.[44]
Summary
Emerging evidence indicates that the three-dimensional organization of chromatin within the nucleus is essential for regulating gene expression[5,6]. The inverted nuclear organization of rods depends on the silencing of key nuclear envelope proteins, including lamin B receptor (Lbr) and lamin A/C (Lmna)[13] It is not clear how these specific loci are regulated in rods, a tremendous amount is known about the transcriptional networks underlying rod and cone identity[14,15]. DNase-seq has been used to map regions of open chromatin (containing candidate CREs) in whole retina[38], and ChIP-seq has been used to elucidate the genome-wide occupancy of individual TFs—CRX39, NRL40, and MEF2D41— in whole retina While these studies have proven highly informative, profiling whole retina is limited in that the ascertainment of CREs is biased towards highly abundant cell types, and the specific cell types underlying individual signals is ambiguous
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