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<p>Transposable elements (TEs), constituting half of the human genome, are essential for development and diseases. While the regulation of TE activity by cellular intrinsic mechanisms is well documented, their response to microenvironmental signals, particularly mechanical cues involving numerous biological processes, remains unknown. Here we show that various TE families, notably LTR7, undergo transcriptomic, epigenetic and three-dimensional genome changes in response to matrix mechanical cues in human embryonic stem cells. Interestingly, LTR7s act as ‘mechano-response enhancer elements’ (MREEs), controlling the gene expression and cell fate of human embryonic stem cells. Mechanistically, mechano-effectors YAP/TEAD1 control LTR7’s epigenetic activity by engaging with BRD4. Furthermore, YAP recruits CTCF, a key genome architecture protein, to facilitate long-range interactions between gene promoters and TEs as MREEs. In particular, a mechano-responsive LTR7 element is a distal enhancer for <i>FAM189A2</i>, thereby inhibiting definitive endoderm differentiation. These findings highlight the underappreciated role of TEs as MREEs that control human cell fate and gene expression.</p>

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A subset of transposable elements as mechano-response enhancer elements in controlling human embryonic stem cell fate

  • 期刊论文

  • 发表日期：

    2025年9月17日

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  • Tongyu Sun,
  • Yueyuan Xu,
  • Nicole Angel,
  • Luna Chen,
  • Kan Zhang,
  • Brenton D. Hoffman,
  • Jianhong Ou,
  • Zhipeng Meng,
  • Shyni Varghese,
  • Yarui Diao

摘要

Transposable elements (TEs), constituting half of the human genome, are essential for development and diseases. While the regulation of TE activity by cellular intrinsic mechanisms is well documented, their response to microenvironmental signals, particularly mechanical cues involving numerous biological processes, remains unknown. Here we show that various TE families, notably LTR7, undergo transcriptomic, epigenetic and three-dimensional genome changes in response to matrix mechanical cues in human embryonic stem cells. Interestingly, LTR7s act as ‘mechano-response enhancer elements’ (MREEs), controlling the gene expression and cell fate of human embryonic stem cells. Mechanistically, mechano-effectors YAP/TEAD1 control LTR7’s epigenetic activity by engaging with BRD4. Furthermore, YAP recruits CTCF, a key genome architecture protein, to facilitate long-range interactions between gene promoters and TEs as MREEs. In particular, a mechano-responsive LTR7 element is a distal enhancer for FAM189A2, thereby inhibiting definitive endoderm differentiation. These findings highlight the underappreciated role of TEs as MREEs that control human cell fate and gene expression.