NIH study shows how genes in retina get regulated during development


Gene expression is the process by which the information encoded in a gene is turned into a functional product. This mostly occurs via the transcription of RNA molecules that code for proteins or non-coding RNA molecules that serve other functions.

Researchers at the National Institutes of Health (NIH) have created a genome topology map of human retina development that lays the foundation for understanding diverse clinical phenotypes (characteristics) in simple and complex eye diseases. The researchers mapped the 3D organization of genetic material of key developmental stages of human retinal formation, using intricate models of a retina grown in the lab. The findings will help scientists to understand clinical traits in many eye diseases, and reveal a highly dynamic process by which the architecture of chromatin, the DNA and proteins that form chromosomes, regulates gene expression. The findings were published in Cell Reports. “These results provide insights into the heritable genetic landscape of the developing human retina, especially for the most abundant cell types that are commonly associated with vision impairment in retinal diseases,” said the study’s lead investigator, Anand Swaroop, Ph.D., chief of the Neurobiology, Neurodegeneration, and Repair Laboratory at the National Eye Institute (NEI), part of NIH.

Genes, the sequences that code for RNA and proteins, are interspersed throughout long strands of DNA. Those DNA strands get packaged into chromatin fibers, which are spooled around histone proteins and then repeatedly looped to form highly compact structures that fit into the cell nucleus. All those loops create millions of contact points where genes encounter non-coding DNA sequences that regulate gene expression. Although these were considered to be “junk DNA”, these sequences are now recognized to play a crucial role in controlling which genes get expressed (“turned on”) in a cell and when.

To shed light on how these non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate, the research team used deep Hi-C sequencing, a tool used for studying 3D genome organization, to create a high-resolution map of chromatin in a human retinal organoid at five key points in development.  (Organoids are tissue models grown in a lab and engineered to replicate the function and biology of a specific type of tissue in a living body.)  At each of the five key retinal organoid developmental stages, billions of chromatin contact point pairs were sequenced and analyzed. The findings reveal a dynamic picture of spatial organization of the genome within the nucleus. It is transformed during retinal development, resulting in the “turning on” of specific genes at key time periods. For example, at a stage when immature cells start developing retinal cell characteristics, chromatin contact points shift from a mostly proximal-enriched state to add more distal interactions. There also appears to be a hierarchy of compartments that organize the contact point interactions. Some of these compartments are stable, but others swap during development, which further serves to enhance or inhibit gene expression. “The datasets resulting from this research serve as a foundation for future investigations into how non-coding sections of the genome are relevant for understanding divergent characteristics in single gene mutation (Mendelian) disorders, as well as complex retinal diseases,” Swaroop said.

Funded by the NEI Intramural Research Program.

Source: NIH News Release, December 13, 2023; see source article