Linking the 3D Genome Structure to Gene Expression in The Mammalian Retina

Abstract

Purpose : To investigate the roles of 3D nuclear organization in regulating gene expression and cellular functions in the retina

Methods : We performed Hi-C on adult mouse retina and integrated the data with fluorescence in situ hybridization (FISH) visualization, ATAC-Seq, epigenetic states, chromatin topology and RNA-Seq to gain insights on the principles that govern the link between 3D nuclear localization, epigenetic regulation and gene expression in the mouse retina

Results : We investigated the nuclear position of hundreds of genes in rods, demonstrating that the spatial nuclear distribution of genes into heterochromatin and euchromatin regions in rods is precisely regulated. All actively expressed genes and most of the repressed genes examined localized to the euchromatic region in the rods nuclear periphery. ChIP-Seq data indicate that the repressed genes that localized to euchromatin are usually marked with H3K27me3. Interestingly, only a handful of repressed genes in rods were found in heterochromatin, and mathematical modeling suggests that the localization of genomic loci among euchromatin and heterochromatin can be predicted based on epigenetic state dynamics of those loci in the retina. we defined the genome-wide long-range interactions in the mouse adult retina, including many retinal-specific topologically associated domains (TADs). We further investigated the nuclear spatial distribution of TADs and TAD subdomains and demonstrate experimentally that a single TAD can span euchromatin and heterochromatin. Finally, we provide experimental evidence that vestigial enhancers that are associated with the expression of progenitor genes at early stages of retinal development can localize to heterochromatin in fully differentiated cells thus rendering those loci transcriptionally inaccessible in photoreceptors

Conclusions : Our analysis provides a new paradigm to study the link between 3D nuclear organization and gene regulation and expands our understanding to the fundamental principles that govern gene expression in the mammalian retina

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.