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Silencing the long non-coding RNA antisense to ZEB2 facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency

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Abstract

Ageing imposes a barrier to somatic cell reprogramming through mechanisms that are poorly understood. Here we studied the age-associated decline in reprogramming efficiency of fibroblasts derived from transgenic mice carrying doxycycline-inducible Oct4, Sox2, Klf4, and c-Myc. We found that fibroblasts from old mice express higher levels of Zeb2, a transcription factor that activates epithelial-to-mesenchymal transition (EMT). As reprogramming requires suppression of pro-EMT signals, we hypothesized that Zeb2 overexpression contributes to the inefficient reprogramming of old fibroblasts. Synthesis of Zeb2 protein is controlled by a natural antisense transcript named Zeb2-NAT, and we show that silencing Zeb2-NAT suffices to enhance reprogramming of old fibroblasts. Transfection of adult fibroblasts with specific LNA Gapmers induced a robust downregulation of Zeb2-NAT transcripts and Zeb2 protein, and subsequent induction with doxycycline resulted in efficient reprogramming into pluripotent cells with capacity to spontaneously form differentiated tumors comprising the three germ layers. We further observed that Zeb2-NAT expression is precociously activated by differentiation stimuli in embryonic stem (ES) cells. Knocking-down Zeb2-NAT maintained ES cells challenged with commitment signals in the ground state of self-renewal and pluripotency. In conclusion, our study identifies a long non-coding RNA that is overlapping and antisense to the Zeb2 locus as a novel target for rejuvenation strategies.


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Silencing the long non-coding RNA antisense to ZEB2 facilitates reprogramming of aged fibroblasts and safeguards stem cell pluripotency


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