Proteins help stem cells stay unchanged until the body needs them to specialise

Researchers in Japan have identified how the proteins RLF and ZFP292 help to stabilise CoREST repression at developmental gene promoters in embryonic stem cells, a finding that may support future efforts to maintain stem cells for research and clinical use

Stem cells are the founding cell type from which all specialised cells and tissues in the body develop and their progression towards mature cell identities takes place through a tightly controlled process known as differentiation. At that time gene expression must be activated or suppressed at the correct time and in the correct cellular context.

Researchers from Japan have identified a two-protein regulatory system that helps to control early steps in cellular development and maturation. In a recent study a team from the University of Osaka, Osaka, Japan, has reported that two proteins with closely related functions, regulator of lipolysis factor (RLF) and zinc finger protein 292 (ZFP292), played a key role in the repression of developmental genes in embryonic stem cells.

Embryonic stem cells can give rise to all specialised cell types in the adult body. To retain this developmental potential, they must keep many genes in a carefully balanced – a ‘poised’ – state. In this condition, developmental genes remain ready to be activated when required but are held silent until differentiation begins. This balance depends on molecular systems that bind to gene promoters, the regions of DNA that help to control whether a gene is switched on or off.

One established mechanism involves repressor complexes such as corepressor of RE1-silencing transcription (CoREST) which help to prevent genes from becoming active in the wrong tissue or at the wrong developmental stage. Although canonical repressor element 1-silencing transcription factor (REST) repression has been studied extensively, the factors that help to maintain CoREST-mediated repression in stem cells have not been fully defined.

“A key mechanism for inhibiting the expression of genes associated with stem cell differentiation involves repressor complexes such as CoREST,” Takamasa Ito, a doctoral candidate and lead author of the study, said. 

“However, it [has been] unclear how CoREST-mediated repression is stably maintained and which other factors help in repressing expression of these genes,” he said.

To investigate this question, the researchers examined RLF and ZFP292, two proteins that previous work had suggested could help to regulate stem cell gene expression. The team mapped where these factors bound across the genome and then removed them individually and together to assess how their loss affected gene activity.

“The results were very striking – we found that RLF and ZFP292 play virtually the same role, in that they stabilise the CoREST complex at gene promoters in embryonic stem cells to repress gene expression,” said Professor Chikashi Obuse, senior author of the study, said.

The findings showed that either RLF or ZFP292 was sufficient to help maintain repression at key promoters. When one or both proteins were present, embryonic stem cells were less likely to drift towards differentiation. When the proteins were lost, promoters that would usually remain repressed became active which led to expression of genes linked to cellular differentiation.

“Our results show that RLF and ZFP292 modulate the activity of the CoREST complex to carefully control gene expression in stem cells,” Ito said.

The study has suggested that RLF and ZFP292 act as overlapping safeguards in the gene-control machinery of embryonic stem cells. By helping to stabilise CoREST at developmental gene promoters, the proteins appear to support the repression required to preserve stem cell identity until differentiation is appropriate.

The researchers said the work could improve understanding of how stem cells maintain their developmental state and how this control can fail when gene expression becomes dysregulated. The findings may also support future techniques to maintain stem cell quality for laboratory research and clinical applications, including regenerative medicine and disease modelling. 

In the longer term, the work could help to inform therapeutic strategies for diseases in which inappropriate gene activation or repression contributes to pathology.

For further reading please visit: 10.1016/j.celrep.2026.117293