Epigenetic lockdown of type I interferon sensing and signalling in human pluripotent cells.

ISG upregulation had little effect on pluripotency markers and occurred without IFN signalling, suggesting that, in contrast to differentiated cells, these ISGs are direct transcriptional targets of the HUSH complex in early development. Chromatin profiling by CUT&Tag confirmed MPP8 enrichment at HUSH-regulated ISGs and revealed a bimodal binding profile of MPP8 to both ISGs and non-ISGs, the latter largely driven by young LINE-1 elements.

We propose that shutdown of the IFN-I system in pluripotent stem cells is essential to prevent lethality from unwarranted self-nucleic acid sensing. This shutdown is achieved through a triple-layer of epigenetic lockdown acting on ligands, sensors, and effectors across the IFN-I pathway.