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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • James H. Holt,
  • Rocio Enriquez-Gasca,
  • Rachel P. Wilson,
  • Elena G. Bochukova,
  • Pierre V. Maillard,
  • Helen M. Rowe

摘要

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.