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Changes to 3D Structure of DNA in Brain Could Have Implications for Psychiatric Disorders

Author: Shashank Tandon

People with psychiatric disorders, such as Schizophrenia and Autism spectrum disorders (ASDs), have an impaired ability to process sensory stimuli from their environment. Such symptoms in these individuals are likely due to abnormal wiring within their brains, originating from genetic mutations in their brain cells.

Our brains adapt to the environment by altering neuronal activity, which induces specific genes to turn on and off at certain times. This is key to making precise connections between nerve cells to form circuits that process information from the outside world. When this gene program is disrupted, it affects the precise formation of these neuronal connections, which may be the underlying cause of many psychiatric disorders.

In a new study, scientists at University of Utah Health and University of Pennsylvania used neuronal cells from mice to determine how specific genes are turned on and off in response to neuronal activity. These researchers discovered that changes in neuronal activity can alter the 3D-structure of the DNA in neurons, which is required for precise temporal control of gene expression. Their analysis suggests that disruption of these activity-dependent rearrangements of DNA may play a role in Schizophrenia and ASD.

The study appears in Nature Neuroscience.

“Think of the genome [the complete DNA within the nucleus of our cells] as a tangled yarn of chromosomes, and for certain genes to get expressed, specific regions of the yarn need to be connected to each other,” says Jason Shepherd, PhD, a co-senior author of the study and associate professor of Neurobiology and Anatomy at U of U Health. “When you unravel specific sections of the yarn, new folds form, such that parts of the yarn that were far away are now near each other.”

Shepherd’s group collaborated with Jennifer Phillips-Cremins, PhD, and her research team at the University of Pennsylvania who are pioneers in recently developed sequencing techniques that can determine 3D-changes in DNA structure. They found that when neurons are not active, regions of the DNA that are supposed to instruct specific genes to make proteins are far away from each other. When the researchers used a drug to activate these neurons, they discovered that it changed the 3D-structure of the DNA, such that new loops were formed that brought the non-protein-coding enhancer regions of the DNA near their target gene, just like in the yarn example above. This allowed transcription, the process of gene expression, to be turned on.

In analyzing the data, lead author Jon Beagan found that there are different classes of these loops. In one class, neural activity induced gene expression, while in the other class, it decreased gene expression. This made the researchers wonder whether these different types of loops play a unique role in two related neurodevelopmental disorders, Schizophrenia and ASD. They found that the type of loop that decreases expression of certain genes was associated with mutations commonly seen in Schizophrenia. Furthermore, they found that the type of loop that increases expression of a different set of genes was associated with mutations commonly seen in ASD. Interestingly, they noticed that these mutations in the two disorders were in a region of the DNA that does not itself make proteins.

“While the role of genetic mutations in the [protein] coding regions is well-known in psychiatric disorders, what role non-coding regions play in these disorders have been difficult to figure out,” says Shepherd.

This is one of the first studies to show that sensory experience can change DNA structure in brain cells and that the changes could have implications for psychiatric disorders. The next step is to make manipulations of these looping events in the brains of live mice and determine its impact on the wiring of the brain, and whether there are consequences on behavior and cognition.

Future research will need to determine whether these experience-dependent changes occur in the same way in humans and if that information can be used to understand an individual’s susceptibility to developing psychiatric disorders.

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This research was supported by the New York Stem Cell Foundation, National Institutes of Health, Chan Zuckerberg Initiative, National Science Foundation and the Brain Research Foundation.