DNA organization in human retinal cells revealed using a 3D map

This is the first detailed integration of retinal regulatory genome topology.


Adult human retinal cells are highly specialized sensory neurons. As they don’t divide, hence are relatively stable for exploring how the chromatin’s three-dimensional structure contributes to the expression of genetic information.

Long DNA strands are wrapped around histone proteins by chromatin fibers and repeatedly looped to generate extremely compact structures. All those loops create multiple contact points where genetic 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 referred to as “junk DNA.” The specific processes by which non-coding regulatory elements exert control, even when their placement on a DNA strand is remote from the genes they regulate, are illuminated by recent research showing how these sequences affect which genes get transcribed and when.

Using deep Hi-C sequencing, a tool for studying 3D genome organization, National Eye Institute researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. They mapped the organization of human retinal cell chromatin. The resulting comprehensive gene regulatory network sheds light on how genes are generally regulated and how the retina functions in both uncommon and common eye conditions.

The study’s lead investigator, Anand Swaroop, said, “This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness.”

The new map included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors. The chromatin topological map was subsequently integrated with datasets on retinal genes and regulatory components. A dynamic picture of interactions within chromatin throughout time surfaced, including regions with varying degrees of isolation from other DNA regions and hotspots for gene activity.

They found distinct patterns of interaction at retinal genes suggesting how chromatin’s 3D organization plays a vital role in tissue-specific gene regulation.

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

Furthermore, similarities in chromatin organization between mice and humans point to cross-species conservation, highlighting the significance of chromatin organizational patterns for retinal gene regulation. In the human retina, 35.7% of gene pairs that interacted through a chromatin loop in mice also did so.

The chromatin topological map was integrated with information on genetic variations linked to AMD and glaucoma, two of the most common diseases that cause vision loss and blindness.  The findings point to specific candidate causal genes involved in those diseases.

The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases, such as diabetic retinopathy, determining missing heritability, and understanding genotype-phenotype correlations in inherited retinal and macular diseases.

Journal Reference:

  1. Marchal, C., Singh, N., Batz, Z. et al. High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci. Nat Commun 13, 5827 (2022). DOI: 10.1038/s41467-022-33427-1
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