A new study led by Prof. LIU Jing from the Guangzhou Institutes of Biomedicine and Health of the Chinese Academy of Sciences, along with collaborators, has revealed that the nuclear receptor RORA acts as a dose-tunable "rheostat" in OKS-mediated somatic reprogramming: moderate RORA expression enhances the formation of induced pluripotent stem cell (iPSC) colonies, while high RORA expression suppresses the formation of stable colonies, demonstrating a biphasic dose response.

The findings were published in Stem Cell Reports on April 2.

As important transcription factors that integrate a variety of cellular signals, nuclear receptors play key roles in development, metabolism, immunity and other processes, yet their functions and mechanisms in somatic cell reprogramming remain unclear.

To systematically evaluate the functions of nuclear receptors in reprogramming, the research team screened 49 murine nuclear receptors and identified the ROR subfamily as consistent enhancers—with RORA exerting the strongest effect.

Further domain analyses indicated that the DNA-binding and ligand-binding domains are essential for RORA's pro-reprogramming activity, while the N-terminal domain contributes to its inhibitory effect when expressed at high levels.

Mechanistically, integrated multi-omics analyses showed that low-dose RORA is associated with the attenuation of interferon-γ (IFN-γ) signaling—with the addition of IFN-γ dampening this enhancement—whereas high-dose RORA is linked to reduced WNT pathway output. Activating WNT signaling with CHIR99021 partially rescued the defect caused by high RORA expression.

This study supports the notion that transcription factors can function as "rheostats" rather than simple on-off switches, and provides a dosage-based framework for improving iPSC reprogramming efficiency and controlling cell fate.