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Retina Development, Retinoblastoma Regulation Revealed in Pediatric Cancer Genome Project Paper

NEW YORK (GenomeWeb) – Epigenetic changes beyond DNA methylation may have an outsized influence on the way gene expression is orchestrated during retinal development, a new study suggests.

As they reported in the journal Neuron yesterday, researchers with the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project relied on sequencing and other strategies to profile the transcription, methylation, histone modification patterns, and more in up to eights stages of normal retina development in mice and humans and in retinoblastoma — a rare pediatric cancer that arises when something in this developmental process goes awry.

The analysis revealed regulatory signposts marking different retina development stages. And the team found evidence that histone modifications, insulators, enhancers, and the like could tuck away or turn genes relevant as cellular differentiation progressed, often tracking more closely with expression of some specialized genes than did DNA methylation.

"[T]o our surprise, only a small percentage of the changes in gene expression during development had any correlation with DNA methylation," corresponding author Michael Dyer, chair of developmental neurobiology at St. Jude Children's Research Hospital, said in a statement. "It's at the histone level that we saw the really profound changes during differentiation."

"It's like packing a suitcase for a trip," Dyer explained. "You put the clothes you need in a suitcase to take with you; but those you don't need, you leave in the closet. In our studies, we're trying to decipher the functional significance of why the retinal cell packs some genes away and makes others more accessible."

The researchers used whole-genome bisulfite sequencing, RNA sequencing, chromatin immunoprecipitation sequencing, and/or ATAC-seq to help assess everything from DNA methylation and gene expression to histone modifications, enhancers and insulator patterns, genome topology, and transcriptional networks at eight stages of mouse retina development and four human retinal development stages.

Prevailing patterns from nearly 200 mouse ChIP-seq datasets suggest chromatin dynamics often track with the expression changes that researchers detected in retinal development-related genes as well. And rather than simply using methylation to flip off genes that became unnecessary as development progressed, they noted, the results suggest that the activity of new genes is frequently enhanced by other epigenetic marks as cells inch toward their final state, while others fall by the wayside without corresponding methylation changes.

"[M]any 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," Dyer explained. "On the flip side, those genes needed for differentiation, which were repressed in the progenitor cells, had their epigenetic repression removed."

The data also made it possible to delve into the regulatory features maintained in stem cells induced from mouse rod photoreceptors, in adult mouse retina tissue, and in retinoblastoma samples. Though the study's authors cautioned that more work is needed to determine the cell source of the disease, their findings suggest that retinoblastomas share epigenetic features with a particular retina developmental stage. 

In a related commentary article in Neuron, Harvard Medical School genetics and ophthalmology researchers Nicolas Lonfat and Connie Cepko, who were not involved in the study, said the new retina regulatory datasets "provide a valuable resource for deciphering the gene regulation networks controlling retinal development."

Data generated from the study is being made available to the broader research community through St, Jude's ProteinPaint web browser.