FACT sets a barrier for cell fate reprogramming in C. elegans and Human

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The chromatin regulator FACT (Facilitates Chromatin Transcription) is essential for ensuring stable gene expression by promoting transcription. In a genetic screen using C. elegans we identified that FACT maintains cell identities and acts as a barrier for transcription factor-mediated cell fate reprogramming. Strikingly, FACT’s role as a reprogramming barrier is conserved in humans as we show that FACT depletion enhances reprogramming of fibroblasts into stem cells and neurons. Such activity of FACT is unexpected since known reprogramming barriers typically repress gene expression by silencing chromatin. In contrast, FACT is a positive regulator of gene expression suggesting an unprecedented link of cell fate maintenance with counteracting alternative cell identities. This notion is supported by ATAC-seq analysis showing that FACT depletion results in decreased but also increased chromatin accessibility for transcription factors. Our findings identify FACT as a cellular reprogramming barrier in C. elegans and humans, revealing an evolutionarily conserved mechanism for cell fate protection.