Scientists have identified a new mechanism by which mitochondria, the powerhouses inside cells, communicate to cell nuclei to program changes in gene expression in neurons supporting brain development.

The team’s study, published in Science and led by researchers at Brown University and the Children’s Medical Center Research Institute at U.T. Southwestern, reveals that a deficiency in a particular metabolite in the nucleus is a key mechanism underlying the genetic disorder GPT2 deficiency.

All cells in the human body – and the motions they enable, from our beating hearts to our wiggling toes – use energy generated by a molecule called ATP. Its energy is thought to be released to fuel cellular processes in only one way: when ATP’s decomposition is initiated by an enzyme, a specific type of protein. Those natural enzymes are called ATPases, and ATP’s reliance on their activity makes these catalysts a desirable model for drug discovery. For example, a naturally derived ATPase that’s smaller and more malleable than a protein could be designed for a precise job like directing ATP’s energy toward killing cancer cells, or targeted to block the release of energy that stimulates harmful cellular processes. Researchers at The Ohio State University have gotten one step closer to that possibility by identifying the first noncoding RNA derived from human cells that can bind to ATP. 

Enhancers are pieces of DNA that act like switches, regulating when genes are turned on and off and how strongly they are activated. Scientists know these switches play a critical role in cancer and other diseases, but they have yet to fully understand how enhancers work together to control gene activity. A new study, which focused on the DNA switches of prostate cancer cells, reveals new insights into enhancers that become active during cancer development and turn on genes linked to the disease. The study found that enhancers work cooperatively in 3D networks, rather than as isolated switches. Some enhancers function as “central hubs” that control many genes, while others play a supporting role. Rhie's lab focuses on chromatin interactions, a specialized area of research that investigates how DNA folds and interacts to regulate gene expression. Using 201 datasets from both prostate tumor samples and healthy prostate tissue, her team identified 3,216 key enhancers specific to prostate cancer. They then zoomed in on one region of the genome and used an advanced technique known as Region Capture Micro-C to map physical interactions between enhancers and genes at extremely high resolution. They found that in prostate cancer cells, enhancers formed an interconnected 3D network that did not exist in normal prostate cells. Next, they used the gene-editing tool CRISPR to delete enhancers one at a time and observe how this affected enhancer activity, chromatin interactions, gene expression and cancer cell growth. Deleting some enhancers had little effect. Deleting other “central” enhancers disrupted the entire network, reducing the activity of other enhancers, switching off many cancer-promoting genes and slowing cancer cell growth. The discovery that some enhancers serve as key control points could inform future cancer therapies. Rather than targeting individual genes, gene-editing therapies could one day edit these master switches to control multiple cancer-promoting genes at the same time.