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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Bruno Bernardes de Jesus & Sérgio Pires Marinho & Sara Barros & António Sousa-Franco & Catarina Alves-Vale & Tânia Carvalho & Maria Carmo-Fonseca, 2018. "Silencing of the lncRNA Zeb2-NAT facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-017-01921-6
    DOI: 10.1038/s41467-017-01921-6
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    Cited by:

    1. Maria Arez & Melanie Eckersley-Maslin & Tajda Klobučar & João Gilsa Lopes & Felix Krueger & Annalisa Mupo & Ana Cláudia Raposo & David Oxley & Samantha Mancino & Anne-Valerie Gendrel & Bruno Bernardes, 2022. "Imprinting fidelity in mouse iPSCs depends on sex of donor cell and medium formulation," Nature Communications, Nature, vol. 13(1), pages 1-20, December.

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