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

Abstract

Abstract The Human Silencing Hub (HUSH) complex safeguards genome integrity in human somatic cells, repressing transposable elements and regulating type I interferon (IFN-I) induction. Here, we use depletion of MPP8 in human induced pluripotent stem cells (iPSCs) as a tool to investigate epigenetic control of the IFN-I system in early development. We confirmed that human iPSCs display an attenuated IFN-I pathway, whereas iPSC-derived neural progenitor cells (NPCs) respond robustly to IFN-I pathway agonists. We found that, in iPSCs, depletion of MPP8 was sufficient to induce expression of young LINE-1 elements and genes linked to the IFN-I system including double-stranded RNA sensors and interferon-stimulated genes (ISGs). ISG upregulation occurred without IFN-I signalling, suggesting that, in contrast to differentiated cells, this ISG regulation is uncoupled from nucleic acid sensing specifically in early development. Chromatin profiling 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 targeting ligands, sensors, and effectors across the IFN-I pathway.