Imprinted genes control several cellular and metabolic processes in embryonic and adult tissues. In particular, paternally expressed gene-3 (Peg3) is active in the adult stem cell population and during muscle and neuronal lineage development. Here we have investigated the role of Peg3 in mouse embryonic stem cells (ESCs) and during the process of somatic cell reprogramming towards pluripotency. Our data show that Peg3 knockdown increases expression of pluripotency genes in ESCs and enhances reprogramming efficiency of both mouse embryonic fibroblasts and neural stem cells. Interestingly, we observed that altered activity of Peg3 correlates with major perturbations of mitochondrial gene expression and mitochondrial function, which drive metabolic changes during somatic cell reprogramming. Overall, our study shows that Peg3 is a regulator of pluripotent stem cells and somatic cell reprogramming.

We thank Marie Victoire Neguembor, Martina Pesaresi and Sergi Angel Bonilla Pons for suggestions on the manuscript and Umberto Di Vicino for technical support. We thank Angelique di Domenico and the group of Antonella Consiglio for providing us the OPA1, DRP1 and VDAC1 antibodies. We thank Mari Carmen Ortells and the group of Bill Keyes for providing us the OXPHOS antibody. The pInducer10-mir-RUP-PheS plasmid was a gift from Stephen Elledge (Addgene plasmid # 44011). We are grateful for support from Ministerio de Economia y Competitividad and FEDER funds (SAF2011-28580, BFU2014-54717-P, and BFU2015-71984-ERC to M.P.C.), Secretaria d'Universitats i Recerca del Departament d'Economia i Coneixement de la Generalitat de Catalunya (2014 SGR1137 to M.P.C.), the European Union's Horizon 2020 research and innovation programme under grant agreement CellViewer No 686637 (to M.P.C.), Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017 and the CERCA Programme/Generalitat de Catalunya (to M.P.C.), People Programme Marie Curie Actions of the European Union's Seventh Framework Programme (FP7/2007-2013/, n° 290123 to I.T.), La Caixa international PhD fellowship (to F.S.), Ministerio de Ciencia e Innovació FPI (to F.A.) and Ministerio de Ciencia e Innovación FPI-Severo Ochoa (to A.C.G).