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Summary Primed epiblast stem cells (EpiSCs) can be reverted to a pluripotent embryonic stem cell (ESC)-like state by expression of single reprogramming factor. We used CRISPR activation to perform a genome-scale, reprogramming screen in EpiSCs and identified 142 candidate genes. Our screen validated a total of 50 genes, previously not known to contribute to reprogramming, of which we chose Sall1 for further investigation. We show that Sall1 augments reprogramming of mouse EpiSCs and embryonic fibroblasts and that these induced pluripotent stem cells are indeed fully pluripotent including formation of chimeric mice. We also demonstrate that Sall1 synergizes with Nanog in reprogramming and that overexpression in ESCs delays their conversion back to EpiSCs. Lastly, using RNA sequencing, we identify and validate Klf5 and Fam189a2 as new downstream targets of Sall1 and Nanog. In summary, our work demonstrates the power of using CRISPR technology in understanding molecular mechanisms that mediate complex cellular processes such as reprogramming., Graphical Abstract, Highlights • Genome-scale CRISPRa screen in mouse EpiSCs identifies novel reprogramming factors • 50 novel genes, including Sall1 and Fam189a2, identified to mediate reprogramming • Sall1 synergizes with Nanog to increase reprogramming efficiency in EpiSCs and MEFs • RNA-seq provides insight into downstream pathways of Sall1 and Nanog-mediated reprogramming, In this study, Metzakopian and colleagues use CRISPR activation to perform a genome-scale reprogramming screen on mouse epiblast stem cells identifying 50 novel candidates. In addition, the authors provide evidence of Sall1 being a potent reprogramming gene, capable of synergizing with Nanog. Lastly, using RNA-seq, the authors provide insight into potential downstream targets of Sall1 and Nanog.