Turning on Silenced Genes in Prader-Willi Research

Stormy Chamberlain holds a tray of stem cells at the UConn Stem Cell Institute at UConn Health. (Photo by Spencer Platt/Getty Images)

A group of researchers from the UConn School of Medicine have received a nearly $3 million grant from the National Institutes of Health to investigate the molecular underpinnings of Prader-Willi syndrome, a rare neurogenetic disorder.

Stormy Chamberlain, associate professor in genetics and genome sciences, Justin Cotney, assistant professor of genetics and genome sciences, and Gordon Carmichael, professor of genetics and genome sciences, are multiple-PIs on this project.

Prader-Willi syndrome affects approximately one out of every 15,000 people. This syndrome occurs when a person inherits an incomplete copy of their paternal chromosome 15.

Critically, this deletion eliminates SNORD116, a cluster of small nucleolar RNAs that may be responsible for methylation, the addition of methyl, of RNA. The function of SNORD116 is not well understood.

Those affected by Prader-Willi syndrome have cognitive impairment, behavioral problems such as temper tantrums and obsessive-compulsive behavior, and delayed motor skills and language development. One of the major effects of Prader-Willi syndrome is that those with the disorder are unable to feel satiated when eating. This often leads to life-threatening obesity and related health problems.

Fortunately, every individual with Prader-Willi syndrome has a copy of the region affected by the disease on the maternal copy of chromosome 15. While this copy is usually inactive, the researchers have shown in previous studies that it can be activated through the depletion of a KRAB domain zinc finger protein that represses the maternal copy.

This finding suggests an intriguing therapeutic approach for treating Prader-Willi syndrome—activating the silent maternal copy. It also provides researchers with a critical tool to help understand how SNORD116 expression is regulated and how SNORD116 functions in neurons.

The team hopes to gain deeper insights into how the maternal copy of SNORD116 is repressed. If they can understand how the allele is normally silenced, they may be able to find additional ways to turn it back on and mitigate the effects of Prader-Willi syndrome.

The researchers also hope to better understand how the targets of RNA modification mediated by SNORD116 influence the characteristic elements of Prader-Willi.

Stormy Chamberlain received her Ph.D. from the University of Florida in molecular genetics. She completed her postdoctoral work at the University of North Carolina and UConn Health. Her lab uses induced pluripotent stem cells to model and study human imprinting disorders.

Justin Cotney received his Ph.D. at Emory University in genetics and molecular biology. He completed his postdoctoral work at Yale University. Cotney’s lab focuses on determining how gene regulatory elements control gene expression during mammalian development.

Gordon Carmichael holds a Ph.D. from Harvard University in biophysics. His research group’s interests include molecular signals that control the expression and function of RNA molecules.

This grant is NIH Grant No.: 1R01HD099975-01

Follow UConn Research on Twitter & LinkedIn.