Researchers from The University of Osaka find that the zinc finger proteins RLF and ZFP292 assist in stabilizing the CoREST corepressor complex at gene promoters in embryonic stem cells, preventing differentiation

Osaka, Japan – Stem cells are the original cell type that all other cells and tissues in the body develop from, carried out through a very tightly regulated process. However, how stem cells differentiate in addition to gene-control systems, such as canonical REST repression, which prevents gene expression in inappropriate tissues, has remained unknown.

Now, researchers from Japan have found an overlapping two-factor system that plays an important role in controlling when and how these cells differentiate. In a study published this month in Cell Reports, researchers from The University of Osaka have revealed that two proteins with very similar functions are key regulators of early steps in cellular development and maturation.

Embryonic stem cells can develop into all the different types of cells present in the adult body, from brain cells to liver cells, through a process called differentiation. This process is tightly regulated by activating and repressing factors that bind to the promoters of developmental genes to maintain them in a ‘poised’ state, where these genes can either be switched on or kept off as needed.

“A key mechanism for inhibiting the expression of genes associated with stem cell differentiation involves repressor complexes such as CoREST,” says lead author, Takamasa Ito. “However, it remains unclear how CoREST-mediated repression is stably maintained and which other factors help in repressing expression of these genes.”

To explore this, the researchers tested the role of two proteins, RLF and ZFP292, which previous studies had suggested may help regulate stem cell gene expression. They looked at where these factors bound themselves across the genome and deleted these factors, both individually and together, to determine the effect on gene expression.

“The results were very striking,” explains senior author, Chikashi Obuse. “We found that RLF and ZFP292 play virtually the same role, in that they stabilize the CoREST complex at gene promoters in embryonic stem cells to repress gene expression.”

The presence of either RLF or ZFP292, or both together, at these promoters prevented stem cells from drifting toward differentiation. When these proteins were lost, promoters that were normally repressed became active, leading to the expression of genes associated with differentiation.

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

These findings may lead to the development of new techniques for maintaining stem cell quality for research and clinical applications. They also help advance our understanding of diseases caused by dysregulated gene expression and could potentially be applied to develop new treatments.
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The article, “RLF/ZFP292 stabilize CoREST-linked LSD1 engagement at bivalent promoters to safeguard pluripotency,” was published this month in Cell Reports at DOI: https://doi.org/10.1016/j.celrep.2026.117293

About The University of Osaka
The University of Osaka was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world. Now, The University of Osaka is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Website: https://resou.osaka-u.ac.jp/en