How cells maintain a consistent size has remained a basic unanswered question in biology, despite clear links between abnormal cell size and disease. A study published in Nature Communications now points to a genetic regulator outside the protein-coding genome that directly governs how large cells grow.
Researchers at The Hospital for Sick Children report that a long non-coding RNA called CISTR-ACT functions as a controller of cell size. Long non-coding RNAs do not encode proteins and are part of the non-coding genome, which accounts for roughly 98 percent of human DNA. The work adds direct functional evidence that these regions shape core cellular properties.
“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 Philipp Maass, senior scientist in the Genetics and Genome Biology program at SickKids. “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.”
CISTR-ACT had previously been linked to Mendelian disease and cartilage malformations, but its role in cell growth was unclear. Using CRISPR/Cas9 and Cas13 gene editing alongside computational analyses, the team showed that CISTR-ACT acts at the DNA and RNA levels. It affects genes involved in cell growth, structure, and cell adhesion.
Reducing or removing CISTR-ACT in preclinical models led to larger red blood cells and altered brain structure, mirroring effects seen in human cells. Increasing CISTR-ACT levels resulted in smaller cells. The study also shows that it mediates gene regulation by recruiting the transcription factor FOSL2 to specific genomic loci, with particular relevance to brain and bone marrow development.
“CISTR-ACT and FOSL2 control cell size much like a magnet,” said lead author Katerina Kiriakopulos. “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.”
Publication Details
Kiriakopulos, K., Soleimanpour, K., McMurray, B.J. et al. LncRNA CISTR-ACT regulates cell size in human and mouse by guiding FOSL2. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67591-x
Researchers at The Hospital for Sick Children report that a long non-coding RNA called CISTR-ACT functions as a controller of cell size. Long non-coding RNAs do not encode proteins and are part of the non-coding genome, which accounts for roughly 98 percent of human DNA. The work adds direct functional evidence that these regions shape core cellular properties.
“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 Philipp Maass, senior scientist in the Genetics and Genome Biology program at SickKids. “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.”
CISTR-ACT had previously been linked to Mendelian disease and cartilage malformations, but its role in cell growth was unclear. Using CRISPR/Cas9 and Cas13 gene editing alongside computational analyses, the team showed that CISTR-ACT acts at the DNA and RNA levels. It affects genes involved in cell growth, structure, and cell adhesion.
Reducing or removing CISTR-ACT in preclinical models led to larger red blood cells and altered brain structure, mirroring effects seen in human cells. Increasing CISTR-ACT levels resulted in smaller cells. The study also shows that it mediates gene regulation by recruiting the transcription factor FOSL2 to specific genomic loci, with particular relevance to brain and bone marrow development.
“CISTR-ACT and FOSL2 control cell size much like a magnet,” said lead author Katerina Kiriakopulos. “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.”
Publication Details
Kiriakopulos, K., Soleimanpour, K., McMurray, B.J. et al. LncRNA CISTR-ACT regulates cell size in human and mouse by guiding FOSL2. Nat Commun (2025). https://doi.org/10.1038/s41467-025-67591-x