New research from Memorial Sloan Kettering Cancer Center (MSK) shows how genes activate across vast distances inside a cell; identifies a new form of cell death that could open new opportunities for cancer therapy; uncovers hidden genetics involved in autism; develops an AI tool that can predict a cell's fate and help change it; and finds STAT3 acts as an inflammation-sensing switch in natural killer cells.
MSK scientists show how genes activate across vast (but still tiny) distances
For more than four decades, one of the central mysteries in genome biology has been how genes get switched on by "enhancers," which are often located far away from the genes they control — separated by tens of thousands of DNA base pairs on the chromosome they share.
A new MSK study now offers a detailed look at how this long-distance communication works, significantly deepening the understanding of this fundamental biological process. It also offers key new insights into the puzzle of "transcriptional bursting" — which is the tendency of genes to fire in short, sporadic bursts.
The study was led by first author Lingling Cheng, PhD , a postdoctoral researcher in the lab of senior study author Alexandros Pertsinidis, PhD , a structural biologist at MSK's Sloan Kettering Institute . Using cutting-edge live-cell imaging at nanometer resolution, the team watched gene activity unfold in real time in mouse embryonic stem cells.
The team found that a protein complex called cohesin plays a critical role in bringing together enhancers (DNA sequences that switch on specific genes) and promoters (the "on" switch). Cohesin acts as a molecular motor, physically reeling in the DNA between the two regions. The complex does this by extruding a loop of DNA along the chromosome until the two regions are brought face-to-face, within just 100 nanometers of each other, the study showed.
"Our data suggests that using this mechanism, cohesin significantly contributes to how frequently enhancers and promoters come together," Dr. Cheng says. "And the process is far more efficient than waiting for the two regions to bump into each other as they randomly drift through the cell nucleus — though that does also happen."
The team found that not only is the loop mechanism key to how frequently genes fire, it also provides a direct explanation for transcriptional bursting. Each time the two regions are brought together, a burst is triggered — and when they drift apart, the burst ends.
The study also determined how an activation signal is transmitted once the enhancer and promoter are brought together. Clusters of proteins called General Transcription Factors (GTFs) — including Taf1 and Med19 — are located near the enhancer. When the loop brings the promoter close enough, it becomes embedded in these clusters, which boosts the ability to flip the gene's on switch. Removing either Taf1 or Med19 had only a modest effect on gene firing, but removing both caused a dramatic drop, revealing a previously unknown redundancy that can protect the system against disruptions.
