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<p>The human silencing hub (HUSH) maintains the genome integrity by silencing invasive genetic elements. However, despite essential roles of the HUSH complex during early embryonic development, the function of the complex in the maintenance of pluripotency is mostly unknown. Here, using CRISPR-based genome editing, we demonstrate that in mouse embryonic stem cells (mESCs), deficiency of HUSH core members MPP8 or TASOR, but not PPHLN1, triggers alteration of colony morphology, and mild defect in exit from pluripotency. Importantly, <i>Mpp8</i>/<i>Tasor</i> double mutants are locked in pluripotent state even upon differentiation stimuli. We further demonstrate that these phenotypes are accompanied by decreased expression of adhesion-related genes. Strikingly, the abnormalities observed in <i>Mpp8</i>/<i>Tasor</i>-null mESCs were largely rescued by ectopic coexpression of cell-adhesion associated genes <i>keratins 18</i> and <i>19</i>. Thus, our study provides new insights into the mechanisms by which the HUSH complex coordinates the exit from pluripotency through regulation of the cell adhesion machinery.</p>

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The HUSH complex facilitates the exit of pluripotency

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月25日

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  • Bowen Wang,
  • Min Qi,
  • Yanqi Sun,
  • Huaqi Liao,
  • Yuzhuo Xu,
  • Lixia Dong,
  • Lijun Xu,
  • Yin Xia,
  • Xiaochun Jiang,
  • Shizhang Ling,
  • Jinzhong Qin

摘要

The human silencing hub (HUSH) maintains the genome integrity by silencing invasive genetic elements. However, despite essential roles of the HUSH complex during early embryonic development, the function of the complex in the maintenance of pluripotency is mostly unknown. Here, using CRISPR-based genome editing, we demonstrate that in mouse embryonic stem cells (mESCs), deficiency of HUSH core members MPP8 or TASOR, but not PPHLN1, triggers alteration of colony morphology, and mild defect in exit from pluripotency. Importantly, Mpp8/Tasor double mutants are locked in pluripotent state even upon differentiation stimuli. We further demonstrate that these phenotypes are accompanied by decreased expression of adhesion-related genes. Strikingly, the abnormalities observed in Mpp8/Tasor-null mESCs were largely rescued by ectopic coexpression of cell-adhesion associated genes keratins 18 and 19. Thus, our study provides new insights into the mechanisms by which the HUSH complex coordinates the exit from pluripotency through regulation of the cell adhesion machinery.