The Maass Lab identifies non-coding gene that controls cell size

Toronto, ON — For cells to function normally, growth must stop at the right size. Researchers at the University of Toronto and the Hospital for Sick Children have identified a non-coding gene that regulates this process, helping to understand abnormal cell growth in diseases such as anemia and cancer.

The Nature Communications study, led by Dr. Philipp Maass, Associate Professor in the Department of Molecular Genetics and Senior Scientist at The Hospital for Sick Children (SickKids), focuses on a long non-coding RNA (lncRNA) called CISTR-ACT, which operates through a gene- and genome-regulatory mechanism.

CISTR-ACT is linked to cell size

CISTR-ACT was already familiar to geneticists. Previous studies had linked it to brachydactyly, a genetic condition affecting finger length, and to mean corpuscular volume (MCV), a clinical measure of red blood cell size commonly used in diagnosing anemia and other diseases. Until now, however, how this gene influenced cell size at a molecular level had not been clear.

Testing what happens without CISTR-ACT

To address this question, the researchers deleted and modulated CISTR-ACT and its RNA in multiple human cell types and in mouse models. Across all experiments, loss of CISTR-ACT caused cells to grow larger than normal and divide more slowly. These effects were observed in different tissues, including blood and brain, and in both humans and mice, showing that the mechanism operates broadly across cell types and species.

How the system works

At the molecular level, the researchers found that CISTR-ACT functions in two coordinated ways.

First, where the CISTR-ACT gene sits in the genome matters. Its position within the three-dimensional structure of DNA helps organize genes involved in cell morphogenesis and shape, allowing them to be regulated together.

Second, the RNA molecule produced by CISTR-ACT guides a regulatory protein called FOSL2 to specific locations in the genome. FOSL2 helps control genes involved in cell size and organization. Without CISTR-ACT, the transcription factor FOSL2 failed to bind to more than 4,600 of its usual gene targets, leading to the cell size differences.

“We provide a comprehensive analysis of the mechanism of a lncRNA, and we reveal a previously unknown genetic basis for cell size control, which is perturbed in many diseases, yet not well understood,” said Dr. Katerina Kiriakopulos, first author of the study.

Why it matters

The findings contribute to growing evidence that non-coding DNA actively influences biology, challenging the long-standing belief that only protein-coding genes drive fundamental cellular processes.

Since abnormal cell size is associated with conditions like macrocytic anemias, cancer, and neurological disorders, recognising CISTR-ACT as a regulator of cell size helps clarify how growth control can fail and may guide future diagnostic or therapeutic research.

The study, “LncRNA CISTR-ACT regulates cell size in human and mouse by guiding FOSL2,” was published in Nature Communications on December 16, 2025.

About the study

The study was led by Dr. Philipp G. Maass, Associate Professor in the Department of Molecular Genetics at the University of Toronto and Senior Scientist at The Hospital for Sick Children (SickKids). Dr. Maass holds a Canada Research Chair in Non-coding Disease Mechanisms.

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

For more information, please contact:
Dr. Philipp Maass
Email: philipp.maass@sickkids.ca