May 22, 2024

New Study Reveals Regulation of Genes in Retina During Development

Scientists at the National Institutes of Health (NIH) have conducted a study that maps the 3D organization of genetic material during the key developmental stages of human retinal formation. Using lab-grown models of the retina, the researchers have gained insights into the regulation of genes in the retina, laying the groundwork for understanding various eye diseases. The findings of the study, which highlight the dynamic nature of chromatin architecture and its role in gene expression, were recently published in Cell Reports.

The lead investigator of the study, Dr. Anand Swaroop, who is the Chief of the Neurobiology, Neurodegeneration, and Repair Laboratory at the National Eye Institute (NEI), stated that the study provides valuable insights into the genetic landscape of the developing human retina, especially for the cell types that are commonly associated with vision impairment in retinal diseases.

The researchers utilized deep Hi-C sequencing, a technique used to study 3D genome organization, to create a high-resolution map of chromatin in a human retinal organoid at different stages of development. Organoids are tissue models that are grown in a laboratory and engineered to mimic the function and biology of specific tissues in the human body.

Genes, which contain the sequences for RNA and proteins, are situated within long DNA strands. These DNA strands are packaged into chromatin fibers, which are then spooled around histone proteins and looped to form compact structures that fit inside the cell nucleus.

These loops create millions of contact points, where genes come into contact with non-coding DNA sequences such as super enhancers, promoters, and silencers, which regulate gene expression. These non-coding sequences, previously considered junk DNA, are now recognized to play a crucial role in controlling gene expression. The 3D architecture of chromatin provides insight into how these non-coding regulatory elements exert control, even when they are located remotely from the genes they regulate.

During each of the five key stages of retinal organoid development, billions of chromatin contact point pairs were sequenced and analyzed by the researchers. The findings revealed a dynamic process, where the spatial organization of the genome within the nucleus undergoes transformation during retinal development, enabling the expression of specific genes at specific times. For instance, during a stage where immature cells start developing retinal cell characteristics, there is a shift in chromatin contact points from being predominantly proximal to including more distal interactions.

The study also identified a hierarchy of compartments that organize contact point interactions. Some of these compartments, known as A and B compartments, remain stable, while others interchange during development, either enhancing or inhibiting gene expression.

The datasets generated from this research serve as a foundation for future investigations into the relevance of non-coding sections of the genome in understanding different phenotypes in single-gene mutation disorders and complex retinal diseases, according to Dr. Swaroop.

Overall, this study sheds light on the regulation of genes in the retina during development, providing valuable insights into the genetic landscape of the human retina and paving the way for future advancements in the understanding and treatment of various retinal diseases.

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