Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency

Bruno Bernardes de Jesus (), Sérgio Pires Marinho, Sara Barros, António Sousa-Franco, Catarina Alves-Vale, Tânia Carvalho and Maria Carmo-Fonseca ()
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Bruno Bernardes de Jesus: Universidade de Lisboa
Sérgio Pires Marinho: Universidade de Lisboa
Sara Barros: Universidade de Lisboa
António Sousa-Franco: Universidade de Lisboa
Catarina Alves-Vale: Universidade de Lisboa
Tânia Carvalho: Universidade de Lisboa
Maria Carmo-Fonseca: Universidade de Lisboa

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-017-01921-6

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