A 3D map shows the organization of DNA in the cells of the human retina

National Eye Institute researchers have discovered the organization of human retinal cell chromatin, the fibers that pack DNA molecules 3 billion nucleotides long into compact structures that fit into the chromosomes in each cell’s nucleus. The resulting comprehensive gene regulatory network provides insight into the regulation of gene expression in general and retinal function in rare and common eye diseases. The study was published in Communications of nature.

“This is the first detailed integration of the regulatory topology of the retinal genome with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” said the study’s lead investigator Anand Swarup, Ph.D. ., a senior investigator and chief of the Neurodegeneration and Recovery Neurobiology Laboratory at NEI, which is part of the National Institutes of Health.

The cells of the retina of an adult are highly specialized sensory neurons which do not divide and are therefore relatively stable for studying how the three-dimensional structure of chromatin contributes to the expression of genetic information.

Chromatin fibers package long strands of DNA that wind around histone proteins and then twist repeatedly to form very compact structures. All of these loops create multiple points of contact where protein-coding genetic sequences interact with gene regulatory sequences such as superenhancers, promoters, and transcription factors.

Such non-coding sequences have long been considered “junk DNA”. But more advanced research is showing ways to control these sequences genes transcribed and when, which sheds light on the specific mechanisms by which non-coding regulatory elements exert control, even when their location on the DNA strand is distant from the genes they regulate.

Using Hi-C deep sequencing, a tool used to study the 3D organization of the genome, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using postmortem retinal samples from four donors.

The researchers then combined this map of chromatin topology with datasets of retinal genes and regulatory elements. A dynamic pattern of interactions within chromatin over time was obtained, including hotspots of gene activity and regions with varying degrees of isolation from other DNA regions.

They found distinct patterns of retinal gene interaction, suggesting that the three-dimensional organization of chromatin plays an important role in tissue-specific gene regulation.

“Having such a high-resolution picture of genomic architecture will continue to provide insight into the genetic control of tissue-specific functions,” Swarup said.

In addition, similarities between mouse and human chromatin organization suggest cross-species conservation, highlighting the importance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of the gene pairs that interacted through the chromatin loop in mice also occurred in the human retina.

Researchers integrated chromatin topological map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, the two leading causes of vision loss and blindness. The obtained data point to certain candidate genes associated with these diseases.

An integrated genome-wide regulatory map will also aid in the evaluation of genes associated with other common retinal diseases such as diabetic retinopathydefining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases.