Researchers at Osaka University discovered that the zinc finger proteins RLF and ZFP292 help stabilize the CoREST corepressor complex at gene promoters in embryonic stem cells, preventing differentiation.
Stem cells are the cell type from which all other cells and tissues in the body originate, and they do so through a very tightly controlled process. However, it remains unclear how stem cells differentiate in addition to gene control systems such as canonical REST silencing that prevent gene expression in inappropriate tissues.
Now, Japanese researchers have discovered an overlapping two-factor system that plays a key role in controlling how and when these cells differentiate. In a study published this month in Cell Reports, Osaka University researchers revealed that two proteins with very similar functions are important regulators of early stages of cell development and maturation.
Through a process called differentiation, embryonic stem cells develop into every type of cell present in the adult body, from brain cells to liver cells. This process is tightly controlled by activating and repressing factors that bind to the promoters of developmental genes to keep them in a “stable” state, allowing these genes to be switched on and off as needed.
An important mechanism for inhibiting the expression of genes associated with stem cell differentiation involves repressor complexes such as CoREST. However, it remains unclear how CoREST-mediated repression is stably maintained and which other factors help suppress expression of these genes. ”
Lead author Takamasa Ito
To explore this, the researchers tested the role of RLF and ZFP292, two proteins that previous studies had suggested may help regulate stem cell gene expression. They looked at where these factors bound across the genome and removed these factors individually or together to see the effects on gene expression.
“The results were quite surprising,” explains senior author Chika Obuse. “We found that RLF and ZFP292 play essentially the same role in stabilizing the CoREST complex at gene promoters in embryonic stem cells and repressing gene expression.”
The simultaneous presence of either RLF or ZFP292, or both, at these promoters prevented stem cells from moving toward differentiation. Loss of these proteins activates normally repressed promoters, causing expression of genes associated with differentiation.
“Our results show that RLF and ZFP292 modulate the activity of the CoREST complex and carefully control gene expression in stem cells,” said Ito.
These discoveries may lead to the development of new techniques to maintain stem cell quality for research and clinical applications. They can also help advance our understanding of diseases caused by dysregulated gene expression and have potential applications in the development of new treatments.
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Reference magazines:
Tetsuya Ito et al. (2026). RLF/ZFP292 stabilizes CoREST-associated LSD1 engagement with bivalent promoters and protects pluripotency. cell report. DOI: 10.1016/j.celrep.2026.117293. https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00371-2
