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Background <p>The evolutionary trajectory of <i>FOXP2</i>, a key regulator of language acquisition and higher-order cognitive function, remains incompletely understood. Retrotransposons such as long interspersed element-1 (LINE-1) are recognized as important contributors to genome regulation, influencing embryonic and neuronal developmental programs. However, the potential contribution of LINE-1 to shaping the cis-regulatory landscape of <i>FOXP2</i> remains unclear.</p> Results <p>Through comparative evolutionary genomic analyses, we identify a locus positioned 342&#xa0;kb upstream of the <i>FOXP2</i> transcription start site that has experienced multiple, successive LINE-1 retrotransposition events during primate evolution. This process produces a 10.6&#xa0;kb composite LINE-1 element present in both human and chimpanzee genomes, which we designate FOXP2-342L1. This element exhibits moderate signals of recent positive selection in modern human populations and resides near a topologically associating domain boundary within the <i>FOXP2</i> regulatory landscape. Integrative 3D genome mapping in human and marmoset neural stem cell models demonstrates that FOXP2-342L1 mediates long range chromatin interactions across the <i>FOXP2</i> cis regulatory domain. Notably, FOXP2-342L1 functions as an evolutionary “hub” that accumulates successive LINE-1 insertions during primate evolution, thereby regulating <i>FOXP2</i> activity and promoting cortical neuron differentiation.</p> Conclusion <p>Our findings uncover a LINE-1 driven reconfiguration of 3D chromatin architecture within the <i>FOXP2</i> regulatory landscape and reveal a primate specific model of neuronal development shaped by retrotransposon activity during primate evolution.</p>

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A LINE-1 insertion upstream of FOXP2 promotes neuronal differentiation during primate evolution

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月4日

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  • Jinhao Liu,
  • Zihang Yin,
  • Yonglin Peng,
  • Shuang Cui,
  • Bo Shi,
  • Xinrui Jiang,
  • Ziyi Yang,
  • Sijie Gu,
  • Yude Lin,
  • Lingfeng Xu,
  • Zhen Xu,
  • Xuankai Wang,
  • Tienan Chen,
  • Wei Zhang,
  • Shaojiao Wang,
  • Zhiwei Xiao,
  • Zhibo Huang,
  • Rujiang Zhou,
  • Zhengju Yao,
  • Xiaodong Zhao,
  • Ya Guo,
  • Shuhua Xu,
  • Weidong Li,
  • Xizhi Guo

摘要

Background

The evolutionary trajectory of FOXP2, a key regulator of language acquisition and higher-order cognitive function, remains incompletely understood. Retrotransposons such as long interspersed element-1 (LINE-1) are recognized as important contributors to genome regulation, influencing embryonic and neuronal developmental programs. However, the potential contribution of LINE-1 to shaping the cis-regulatory landscape of FOXP2 remains unclear.

Results

Through comparative evolutionary genomic analyses, we identify a locus positioned 342 kb upstream of the FOXP2 transcription start site that has experienced multiple, successive LINE-1 retrotransposition events during primate evolution. This process produces a 10.6 kb composite LINE-1 element present in both human and chimpanzee genomes, which we designate FOXP2-342L1. This element exhibits moderate signals of recent positive selection in modern human populations and resides near a topologically associating domain boundary within the FOXP2 regulatory landscape. Integrative 3D genome mapping in human and marmoset neural stem cell models demonstrates that FOXP2-342L1 mediates long range chromatin interactions across the FOXP2 cis regulatory domain. Notably, FOXP2-342L1 functions as an evolutionary “hub” that accumulates successive LINE-1 insertions during primate evolution, thereby regulating FOXP2 activity and promoting cortical neuron differentiation.

Conclusion

Our findings uncover a LINE-1 driven reconfiguration of 3D chromatin architecture within the FOXP2 regulatory landscape and reveal a primate specific model of neuronal development shaped by retrotransposon activity during primate evolution.