A map of the genome organization and DNA modifications that control growth of normal and cancerous retinal cells offers scientists a new path to understanding retinoblastoma and degenerative retinal diseases.
A team from the St. Jude Children's Research Hospital – Washington University Pediatric Cancer Genome Project (PCGP) has mapped the intricate changes in the "epigenetic" organization of the nucleus to determine how retinal cells transition from immature cells to mature retinal neurons. The researchers have also mapped the epigenome of retinoblastoma cells as they turn cancerous.

The data are an invaluable resource for discovering the still–unknown cellular origin of retinoblastoma. Scientists can also explore the data for pathways that trigger adult retinal diseases like age–related macular degeneration and retinitis pigmentosa.

The researchers were led by Michael Dyer, PhD, a Howard Hughes Medical Institute Investigator and St. Jude Department of Developmental Neurobiology chair.

The work appeared in the May 3 issue of the journal Neuron.

Epigenetic controls are molecular switches that turn genes on or off to orchestrate a cell’s development from a generic cell to a specialized cell like a neuron. While the "genome" of thousands of individual genes is like data stored on a computer disk, the "epigenome" is like a computer program that controls how stored data are read.

Researchers know that epigenetic malfunctions can drive cancers and degenerative diseases, but they have not cracked the "epigenetic code" – the specific changes in the organization of the nucleus that guide each type of cell to differentiate from a progenitor cell to a specialized cell.

The researchers used tools of epigenomic analysis to trace the specific epigenetic switches controlling each of thousands of genes in both mouse and human retinal cells as the cells progressed through development.

Analyzing the data revealed surprises about the epigenetic processes of retinal neuron development, Dyer said. One such surprise was the relative importance of two types of epigenetic control switches for retinal development. One control is DNA methylation, which is a chemical alteration of a gene that switches it on or off. The other control switch is histone modification. Histones are proteins that serve as a scaffold for coiling up the DNA into the tight space of the nucleus.

"The perception of the research community was that DNA methylation was the major epigenetic controller," Dyer said. "But to our surprise, only a small percentage of the changes in gene expression during development had any correlation with DNA methylation. It's at the histone level that we saw the really profound changes during differentiation."

Another unexpected discovery, Dyer said, was the point during development when the immature cells transition from making new tissue by dividing rapidly, to differentiating into a mature retinal neuron.

"It's like flipping a giant switch," Dyer said. "Early in development, all the cells are immature progenitors that are rapidly growing and dividing. Then, when those cells stop growing and start becoming neurons, there was a dramatic shift in the epigenome.

"We thought cells would actively shut down those progenitor growth genes, because it would not want them to reactivate and lead to a tumor," he said. "But instead, many of those genes just went from a very active state into what we call an 'empty' state. The cell didn’t make any particular effort to shut them down. On the flip side, those genes needed for differentiation, which were repressed in the progenitor cells, had their epigenetic repression removed."