Scientists identify a non-coding gene that directly controls how big cells grow

Why cells grow to just the right size has long baffled scientists. Too small or too large, and cells can trigger serious diseases, but the genetic switch behind this balance has remained elusive. Now, researchers say they have found it. A team at The Hospital for Sick Children (SickKids) has identified, for the first time, a gene in the non-coding genome that directly controls cell size.

The discovery reshapes how scientists understand growth at the most fundamental biological level. It also challenges the long-held idea that non-coding DNA, often labeled junk DNA , plays little functional role. The study shows that a long non-coding RNA called CISTR-ACT acts as a master regulator of cell size, influencing how large or small cells grow across multiple tissues.

Hidden genetic controller Unlike conventional genes that encode proteins, CISTR-ACT belongs to the non-coding genome, which makes up about 98 percent of human DNA. Until recently, this genomic region was poorly understood. Our study shows that long non-coding RNAs and the non-coding regions of the genome can drive important biological processes, including cell size regulation, said Dr.

Philipp Maass, Senior Scientist at SickKids. He added that the team identified the first causal long non-coding RNA that directly influences cell size. CISTR-ACT had previously been linked to Mendelian disease and cartilage malformations, but its role in regulating cell growth was unknown. To uncover its function, researchers combined CRISPR/Cas9 and Cas13 gene-editing tools with computational biology.

The results showed that CISTR-ACT operates at both the DNA and RNA levels. It influences genes involved in cell growth, structure, and cell adhesion—the way cells interact with and attach to neighboring cells. When researchers reduced or removed CISTR-ACT in preclinical models, cells grew larger. Red blood cells expanded in size, and changes appeared in brain structure.

When extra CISTR-ACT was added, cells became smaller, confirming its direct role in size control. Magnet-like cell control The team also uncovered how CISTR-ACT exerts its influence. The RNA guides a protein called FOSL2, helping it bind to and regulate other genes that shape cell growth, particularly during brain and bone marrow development.

CISTR-ACT and FOSL2 control cell size much like a magnet, said Dr. Katerina Kiriakopulos, lead author of the study. When the magnet is removed, the cells grow, and when you put the magnet in, cells shrink. The effect was seen across multiple cell types and species.

The surprising part was that we could do this across various cell types and species, she said, pointing to a conserved biological mechanism. Researchers say the findings open new avenues for medical research. Cell size plays a critical role in conditions such as cancer, anemia, and developmental disorders. Knowing CISTR-ACT works at both the DNA and RNA levels tells us there are multiple pathways for controlling cell size, Maass said.

This opens new directions for potentially translating these findings into precision therapies. The work involved collaboration across SickKids teams specializing in genetics, brain imaging, and computational biology, with funding from Canada s national research agencies.

The findings were published in Nature Communications.