The vast majority of genetic mutations that are associated with disease occur at sites in the genome that aren’t genes. These sequences of DNA don’t code for proteins themselves, but provide an additional layer of instructions that determine if and when particular genes are expressed. Researchers are only beginning to understand how the non-coding regions of the genome influence gene expression and might be disrupted in disease.
Jennifer Phillips-Cremins, assistant professor in the Department of Bioengineering in the University of Pennsylvania’s School of Engineering and Applied Science, studies the three-dimensional folding of the genome and the role it plays in brain development. When a stretch of DNA folds, it creates a higher-order structure called a looping interaction, or “loop.” In doing so, it brings non-coding sites into physical contact with their target genes, precisely regulating gene expression in space and time during development.
Phillips-Cremins and lab member Jonathan Beagan have led a new study identifying a new protein that connects loops in embryonic stem cells as they begin to differentiate into types of neurons. Though the study was conducted in mice, these findings inform aspects of human brain development, including how the genetic material folds in the 3-D nucleus and is reconfigured as stem cells become specialized. Better understanding of these mechanisms may be relevant to a wide range of neurodevelopmental disorders.
Cremins lab members Michael Duong, Katelyn Titus, Linda Zhou, Zhendong Cao, Jingjing Ma, Caroline Lachanski and Daniel Gillis also contributed to the study, which was published in the journal Genome Research.
Continue reading at the SEAS blog.