Scientists identify first non-coding gene that controls cell size

What keeps our cells the right size? Scientists have long puzzled over this fundamental question, since cells that are too large or too small are linked to many diseases. Until now, the genetic basis behind cell size has largely been a mystery. New research has, for the first time, identified a gene in the non-coding genome that can directly control cell size.

In a study published in Nature Communications, a team at The Hospital for Sick Children (SickKids) found that a gene called CISTR-ACT acts as a controller of cell growth. Unlike genes that encode for proteins, CISTR-ACT is a long non-coding RNA (or lncRNA) and is part of the non-coding genome, the largely unexplored part that makes up 98 per cent of our DNA. This research helps show that the non-coding genome, often dismissed as ‘junk DNA’, plays an important role in how cells function.

“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. By carefully examining a wide range of cell types and phenotypes, we identified the first causal long non-coding RNA that directly influences cell size,” says Dr. Philipp Maass, Senior Scientist in the Genetics & Genome Biology program, and Canada Research Chair in Non-Coding Disease Mechanisms.

CISTR-ACT was previously associated by Maass to Mendelian disease and cartilage malformation, but its involvement in cell size and how it regulates genes was unknown. Using an interdisciplinary approach including CRISPR/Cas9 and Cas13 gene editing and computational biology, the team explored its molecular mechanism, showing that CISTR-ACT has functional roles at both the DNA and RNA levels. It influences other genes involved in cell growth, structure and cell adhesion, the process by which cells interact and attach to neighbouring cells.

When CISTR-ACT was reduced or removed in preclinical models, the researchers observed larger red blood cells and changes in brain structure, similar to effects seen in human cells. Adding more CISTR-ACT made the cells smaller, confirming its role in cell size regulation.

Notably, the researchers showed it carries out function by guiding a protein called FOSL2 to bind to other genes to regulate them, which is especially important in brain and bone marrow development.

“CISTR-ACT and FOSL2 control cell size much like a magnet. When the ‘magnet’  is removed, the cells grow, and when you put the magnet in, cells shrink. The surprising part was that we could do this across various cell types and species, showing there is a conserved function in human cells as well as our preclinical models,” says Dr. Katerina Kiriakopulos, lead author of the paper and former PhD student in the Maass Lab at SickKids, and now a postdoctoral fellow at the Friedrich Miescher Institute for Biomedical Research in Switzerland.

The team notes that further research is needed to better understand exactly how CISTR-ACT guides FOSL2 to drive gene regulation and whether other non-coding RNAs play similar roles in different cell types and diseases.

“Knowing CISTR-ACT works at both the DNA and RNA levels tells us there are multiple pathways for controlling cell size. This opens new directions for potentially translating these findings into precision therapies for conditions like cancer and anemia, where cell size is a critical factor,” says Maass.

This research was made possible through collaboration with other SickKids teams, including experts in brain research and imaging. The study is part of ongoing efforts in the Maass Lab to explore functional regions of the non-coding genome that may impact development and disease mechanisms, such as blood pressure regulation and hypertension.

This study was supported by the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council of Canada (NSERC).