2026-04-08 中国科学院（CAS）
＜関連情報＞
- https://english.cas.cn/newsroom/research-news/202604/t20260410_1155618.shtml
- https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(26)00081-0
Roraによる体細胞リプログラミングの用量依存的制御 Dose-resolved control of somatic reprogramming by Rora
Haiyun Wang ∙ Yusha Li ∙ Chunkou Yin ∙ … ∙ Shengyong Yu ∙ Manish Kumar ∙ Jing Liu
Stem Cell Reports Published:April 2, 2026
DOI:https://doi.org/10.1016/j.stemcr.2026.102870
Graphical abstract
Highlights
- ystematic screen of 49 murine nuclear receptors identifies RORs as OKS enhancers
- RORA exerts a dose-dependent, biphasic effect on OCT4-GFP+ colony formation
- Pro-reprogramming requires DBD/LBD; high-dose inhibition requires NTD
- RoraLow limits IFN-γ; add-back blocks benefit. High lowers WNT; CHIR partly rescues
Summary
Nuclear receptors (NRs) are ligand-regulated transcription factors whose domains and dosage modulate gene networks. We systematically profiled 49 murine NRs in OKS (OCT4/KLF4/SOX2) reprogramming of mouse fibroblasts and identified the ROR subfamily as enhancers. Focusing on Rora, we uncovered a dose-dependent, biphasic effect on reprogramming: moderate Rora increases OCT4-GFP+ colony formation, whereas higher expression reduces colonies. Domain dissection separated these arms—DNA-binding domain (DBD)/ligand-binding domain (LBD) was required for the pro-reprogramming effect, while the N-terminal domain (NTD) was required for high-dose inhibition (ΔNTD eliminated the inhibitory limb). Functionally, the reprogramming barrier interferon (IFN)-γ was attenuated at transcript and protein levels; IFN-γ add-back dampened the enhancement, supporting immune-axis modulation. Conversely, WNT pathway output was reduced in the inhibitory arm, and CHIR99021 partially rescued the high-dose colony defect. Thus, RORA acts as a dose-programmed, domain-modular regulator that coordinates chromatin and signaling to gate cell-fate conversion, establishing nuclear-receptor dosage control as a lever to improve reprogramming efficiency.
