Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency.
Bruno Bernardes de JesusSérgio Pires MarinhoSara BarrosAntónio Sousa-FrancoCatarina Alves-ValeTânia CarvalhoMaria Carmo-FonsecaPublished in: Nature communications (2018)
Aging imposes a barrier to somatic cell reprogramming through poorly understood mechanisms. Here, we report that fibroblasts from old mice express higher levels of Zeb2, a transcription factor that activates epithelial-to-mesenchymal transition. Synthesis of Zeb2 protein is controlled by a natural antisense transcript named Zeb2-NAT. We show that transfection of adult fibroblasts with specific LNA Gapmers induces a robust downregulation of Zeb2-NAT transcripts and Zeb2 protein and enhances the reprogramming of old fibroblasts into pluripotent cells. We further demonstrate that Zeb2-NAT expression is precociously activated by differentiation stimuli in embryonic stem (ES) cells. By knocking down Zeb2-NAT, we were able to maintain ES cells challenged with commitment signals in the ground state of pluripotency. In conclusion, our study identifies a long noncoding RNA that is overlapping and antisense to the Zeb2 locus as a target for rejuvenation strategies.
Keyphrases
- epithelial mesenchymal transition
- long non coding rna
- induced apoptosis
- poor prognosis
- long noncoding rna
- signaling pathway
- stem cells
- cell cycle arrest
- transcription factor
- extracellular matrix
- endoplasmic reticulum stress
- cell death
- binding protein
- single cell
- protein protein
- insulin resistance
- cell therapy
- mesenchymal stem cells
- amino acid
- bone marrow
- small molecule
- skeletal muscle