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.
Read more in Cell.
A new form of cell death could open new opportunities for cancer therapy
A team of scientists from MSK and their collaborators have discovered a new mitochondrial death machinery that triggers a distinct form of programmed cell death, dubbed “baciptosis.” Unlike apoptosis, a well-studied form of cell death, baciptosis can stimulate immune responses. The discovery provides new insights into the mechanisms of cell death and what this could mean for interactions between tumors and the immune system.
The research team found that two proteins, called BAK and BAX, come together in mitochondria in two distinct ways, each triggering a fundamentally different form of cell death. In one arrangement, the proteins release a molecule called cytochrome c, which activates enzymes called caspases that trigger apoptosis — a form of cell death that typically does not provoke an inflammatory immune response.
The other arrangement forms when BAK and BAX assemble with other proteins in the outer and inner mitochondrial membranes, allowing mitochondrial DNA (mtDNA) to be released into the cytosol (the fluid inside a cell). When caspases are not activated, mtDNA release triggers inflammatory responses and contributes to catastrophic energy failure, leading to baciptosis and a strong response from the immune system. The researchers also demonstrated that baciptosis can be induced in human cancer cells with impaired caspase activation, suggesting its potential relevance to cancers with similar defects.
The findings expand our understanding of BAK and BAX beyond their established roles in apoptosis and reveal how these proteins can regulate immunogenic cell death.
The results could have important implications for cancer therapy. Finding ways to trigger baciptosis instead of apoptosis in cancer cells could help the immune system recognize and attack tumors and improve cancer immunotherapy.
The study was overseen by senior study author Emily Cheng, MD, PhD, in MSK’s Human Oncology and Pathogenesis Program, and led by co-first authors Shaoyuan Yang, PhD, a postdoctoral fellow at MSK, and Hyungjin Kim, PhD, a former graduate student of Dr. Cheng at Washington University who is now a faculty member at Stony Brook University.
Read more in Science and in a related Perspective article.
Uncovering the hidden genetics of autism spectrum disorder
A new study co-led by MSK computational biologist Quaid Morris, PhD, may help explain why the genetic basis of autism spectrum disorder has long puzzled scientists.
Although hundreds of genomic variants have been linked to autism, they account for a genetic diagnosis in only about 15% of autistic individuals. The researchers focused on microexons — very short DNA segments that can be selectively included or excluded when cells build proteins — which prior work had implicated in the disorder.
Dr. Morris and collaborators at the University of Toronto, King’s College London, and the Francis Crick Institute developed a machine learning model that decodes the regulatory rules governing microexon splicing. When the team ran the model on genetic data from thousands of autistic individuals and their neurotypical siblings, predicted splicing disruptions appeared almost entirely in the 85% of autistic individuals who had never received a genetic explanation for their diagnosis — suggesting microexons may account for much of that missing piece.
The researchers believe the model can also be applied to other neurological conditions, including schizophrenia and epilepsy, where microexons are thought to play a role.
Read more in Nature and in an article by the University of Toronto.
Researchers develop AI tool that can predict a cell’s fate — and help change it
Researchers from MSK and Weill Cornell Medicine have developed a new artificial intelligence (AI) tool to help scientists understand how cells change and develop over time — and predict what happens when key genes go wrong.
The research team — overseen by senior study authors Christina Leslie, PhD, a computational biologist at MSK, and Darko Barisic, PhD, an assistant professor of Cancer Biology Research at Weill Cornell Medicine — built the tool, called DynaVelo, to study how gene activity and the proteins that control it (transcription factors) change as cells develop. The model was tested on B cells, immune cells from which many lymphomas arise.
A core challenge in this kind of research is that single-cell sequencing — a technology that reads the genetic activity of thousands of individual cells at once — only captures a single moment in time. DynaVelo uses AI to analyze these snapshots and learn the underlying rules that govern cell state changes, allowing it to infer the full course of a cell’s development.
The team used DynaVelo to understand how losing Arid1a — a protein involved in organizing chromatin and regulating gene activity — disrupts the normal process of B cell maturation, pushing cells toward an immature fate associated with B cell lymphoma.
One of DynaVelo’s most powerful features is its ability to run virtual experiments. Researchers can simulate what happens when a gene is lost and then test whether those predictions match what happens when the gene is silenced in animal models. They can also run the virtual experiments in reverse — asking which genetic change might fix broken cells. This kind of “in silico” experiment, which can screen thousands of possibilities virtually, would be prohibitively slow and expensive to perform in animal models.
When the team used DynaVelo to search for ways to counteract the loss of Arid1a, the model nominated three candidates: Ctcf, Stat3, and Bcl6. The scientists then made new mouse models to test these predictions, and in each case, the changes restored normal B cell behavior — validating the algorithm.
“Our findings suggest DynaVelo could help accelerate the search for new treatments by identifying promising therapeutic targets virtually,” Dr. Leslie says.
The study was led by first author Alireza Karbalayghareh, PhD, a postdoctoral researcher in the Leslie Lab (now a senior research scientist at CZ Biohub New York).
Read more in Nature Biotechnology.
STAT3 acts as an inflammation-sensing switch in natural killer cells
A protein called STAT3 acts as a molecular switch inside natural killer (NK) cells, changing how it behaves based on the severity of a viral infection, a new MSK study finds. NK cells are a key part of the innate immune system’s defense against infection.
The research team — led by Simon Grassmann, MD, a postdoctoral fellow in the lab of senior study author Joseph Sun, PhD, at MSK’s Sloan Kettering Institute — found that STAT3 activates entirely different sets of genes in response to a mild infection than during a severe infection.
During low-grade infection, STAT3 promotes the expression of a protein called MYB that drives NK cell proliferation and builds long-term immune protection. During severe infection, when levels of an inflammatory molecule called type I interferon are high, STAT3 instead activates a protein called BLIMP-1 that pushes NK cells toward a powerful but short-lived state to quickly eliminate the pathogen.
STAT3 acts by repositioning itself on the genome depending on the severity of the infection. This process is governed by epigenetic changes — changes in how DNA is packaged, which determine the accessibility of specific regions of the genome — as well as by STAT3’s preference for binding to specific DNA sequences depending on the context.
The findings raise an important question for cancer immunotherapy, the researchers note. STAT3 inhibitors are currently being tested against cancer, and their effectiveness may depend on the level of inflammation within a tumor — suggesting that pairing STAT3 inhibitors with other treatments that modulate tumor inflammation could make them more effective.
Read more in Science Immunology.