LncRNA-Smad7 mediates cross-talk between Nodal/TGF-β and BMP signaling to regulate cell fate determination of pluripotent and multipotent cells

Transforming growth factor β (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Nodal/Activin/TGF-β and BMP ligands are both present in the intra- and extracellular milieu during early development, and cross-talk between these two branches of developmenta...

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Bibliographic Details
Published in:Nucleic acids research 2022-10, Vol.50 (18), p.10526-10543
Main Authors: Kong, Xiaohui, Yan, Kun, Deng, Pujuan, Fu, Haipeng, Sun, Hongyao, Huang, Wenze, Jiang, Shuangying, Dai, Junbiao, Zhang, Qiangfeng Cliff, Liu, Jun-Jie Gogo, Xi, Qiaoran
Format: Article
Language:English
Subjects:
Activins - metabolism
Activins - pharmacology
Animals
Cell Differentiation
Ligands
Mice
Molecular Biology
RNA, Long Noncoding - metabolism
Smad7 Protein - genetics
Smad7 Protein - metabolism
Smad7 Protein - pharmacology
Transforming Growth Factor beta - metabolism
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Summary:Transforming growth factor β (TGF-β) superfamily proteins are potent regulators of cellular development and differentiation. Nodal/Activin/TGF-β and BMP ligands are both present in the intra- and extracellular milieu during early development, and cross-talk between these two branches of developmental signaling is currently the subject of intense research focus. Here, we show that the Nodal induced lncRNA-Smad7 regulates cell fate determination via repression of BMP signaling in mouse embryonic stem cells (mESCs). Depletion of lncRNA-Smad7 dramatically impairs cardiomyocyte differentiation in mESCs. Moreover, lncRNA-Smad7 represses Bmp2 expression through binding with the Bmp2 promoter region via (CA)12-repeats that forms an R-loop. Importantly, Bmp2 knockdown rescues defects in cardiomyocyte differentiation induced by lncRNA-Smad7 knockdown. Hence, lncRNA-Smad7 antagonizes BMP signaling in mESCs, and similarly regulates cell fate determination between osteocyte and myocyte formation in C2C12 mouse myoblasts. Moreover, lncRNA-Smad7 associates with hnRNPK in mESCs and hnRNPK binds at the Bmp2 promoter, potentially contributing to Bmp2 expression repression. The antagonistic effects between Nodal/TGF-β and BMP signaling via lncRNA-Smad7 described in this work provides a framework for understanding cell fate determination in early development.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkac780