The 3D map reveals DNA tissue within human retinal cells

Researchers at the National Institute of Ophthalmology mapped the structure of chromatin in human retinal cells, a fiber that packs 3 billion nucleotide-long DNA molecules into a compact structure and matches
the chromosomes within each nucleus.
The resulting comprehensive gene regulatory network provides insights into the general regulation of gene expression and the regulation of retinal function, including rare and common eye diseases
.
The study was published in the journal Nature Communications
.

"This is the first detailed integration of the retina-regulatory genomic topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, which are two of the main causes of vision loss and blindness," said Anand Swaroop, the study's lead investigator, Dr.
Anand Swaroop, senior researcher and director of the NEI Neurodegenerative Degeneration and Repair Laboratory at the National Institutes of
Health.

Adult retinal cells are highly specialized sensory neurons that do not divide and are therefore relatively stable
for exploring how the three-dimensional structure of chromatin contributes to the expression of genetic information.

Chromatin fibers are wrapped in long strands of DNA that are wrapped around histone proteins and then repeatedly circulate to form highly compact structures
.
All of these cycles create multiple contact points where the gene sequences that code for proteins interact with gene regulatory sequences such as super-enhancers, promoters, and transcription factors
.

This non-coding sequence has long been considered "junk DNA
.
" But more advanced studies have demonstrated how these sequences control which genes are transcribed and when, revealing specific mechanisms by which noncoding regulatory elements exert a controlling role, even if their position on the DNA strand is far from the genes
they regulate.

Using deep Hi-C sequencing, a tool used to study 3D genomic tissue, the researchers created a high-resolution map that included 704 million touchpoints
in chromatin in retinal cells.
The map was drawn using posthumous retinal samples from
four donors.

The researchers then integrated chromatin topology maps with datasets of retinal genes and regulatory elements
.
This is a moving image of the interaction within chromatin over time, including hot spots of gene activity and areas that are insulated to varying degrees from other regions of DNA
.

They found different interaction patterns on the retinal gene, which shows how 3D tissue of chromatin plays an important role
in tissue-specific gene regulation.

Svalop said: "Having such a high-resolution image of genomic structure will continue to provide insights
into gene control of tissue-specific functions.
"

In addition, similarities between mouse and human chromatin tissue indicate conservation across species, emphasizing the correlation between chromatin tissue patterns and retinal gene regulation
.
More than one-third (35.
7 percent) of gene pairs interacted through chromatin rings in mice, as well as
in the human retina.

The researchers integrated chromatin topology maps with data on genetic variants associated
with genomic association studies in AMD and glaucoma, the two main causes of vision loss and blindness.
The findings point to specific candidate pathogenic genes
associated with these diseases.

An integrated genomic regulatory map will also help to evaluate genes associated with other common retina-related diseases such as diabetic retinopathy, identify missing heritability, and understand genotype-phenotypic correlations
for hereditary retinal and macular diseases.

The research is supported by NEI's on-campus research projects funded by ZIAEY000450 and ZIAEY000546
.

Journal Reference:

1. Claire Marchal, Nivedita Singh, Zachary Batz, Jayshree Advani, Catherine Jaeger, Ximena Corso-Dí az, Anand Swaroop.
   High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci.
   Nature Communications, 2022; 13 (1) DOI: 10.
   1038/s41467-022-33427-1