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3D map reveals DNA organization in human retinal cells

October 7, 2022 — NIH scientists shed light on how genetic architecture determines gene expression, tissue-specific function, and disease phenotype in blinding diseases.

“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 principal investigator, Anand Swaroop, Ph.D., principal investigator and head of the Neurobiology, Neurodegeneration and Repair Laboratory at NEI, part of the National Institutes of Health.

Adult human 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 pack long strands of DNA, which are wrapped around histone proteins and then repeatedly looped to form tightly packed structures. All of these loops create multiple contact points where gene sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors.

These non-coding sequences have long been considered “junk DNA”. But more advanced studies demonstrate how these sequences control which genes are transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is distant from the genes they serve. regulate.

Using deep Hi-C sequencing, a tool used to study 3D genome organization, the researchers created a high-resolution map that included 704 million touchpoints in the chromatin of retinal cells. The maps were constructed from post-mortem retina samples from four human donors.

The researchers then integrated this topological map of chromatin with datasets of retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including hotspots of gene activity and areas with varying degrees of isolation from other regions of DNA.

They found distinct patterns of interaction at the retinal gene level suggesting how the 3D organization of chromatin plays an important role in tissue-specific gene regulation.

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

Furthermore, similarities between mice and human chromatin organization suggest conservation across species, highlighting the relevance of chromatin organization patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting via a chromatin loop in mice also did so in the human retina.

The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and of blindness. The results point to specific candidate causative genes involved in these diseases.

The integrated genome regulatory map will also help assess genes associated with other common retina-associated diseases such as diabetic retinopathy, determine missing heritability, and understand genotype-phenotype correlations in inherited retinal and macular diseases. .

The study was supported by the NEI Intramural Research Program, grants ZIAEY000450 and ZIAEY000546.

This press release describes a basic research result. Basic research improves our understanding of human behavior and biology, which is fundamental to advancing new and better ways to prevent, diagnose and treat disease. Science is an unpredictable and incremental process – each advance in research builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit

NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…stimulating innovation, fostering collaboration, expanding the vision workforce and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to expand opportunities for people with visual impairments. For more information, visit

About the National Institutes of Health (NIH): The NIH, the country’s medical research agency, comprises 27 institutes and centers and is part of the US Department of Health and Human Services. The NIH is the primary federal agency that conducts and supports basic, clinical, and translational medical research, and studies the causes, treatments, and cures for common and rare diseases. For more information about the NIH and its programs, visit

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Marchal C, Singh N, Batz Z, Advani J, Jaeger C, Corso-Diaz X, and Swaroop A. “High-resolution genome topology of the human retina reveals super enhancer-promoter interactions at disease-specific disease loci tissues and multifactorials.” Published October 7, 2022, Nature Communications. DOI: 10.1038/s41467-022-33427-1.

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