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ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription

Author

Listed:
  • Chunhong Yu

    (Central South University)

  • Xiaoyun Lei

    (Central South University)

  • Fang Chen

    (Central South University)

  • Song Mao

    (Central South University)

  • Lu Lv

    (Central South University)

  • Honglu Liu

    (Central South University)

  • Xueying Hu

    (Central South University)

  • Runhan Wang

    (Central South University)

  • Licong Shen

    (Central South University
    Central South University)

  • Na Zhang

    (Central South University)

  • Yang Meng

    (Central South University)

  • Yunfan Shen

    (Central South University)

  • Jiale Chen

    (Central South University)

  • Pishun Li

    (Central South University)

  • Shi Huang

    (Central South University)

  • Changwei Lin

    (Central South University
    Central South University)

  • Zhuohua Zhang

    (Central South University
    Central South University
    Central South University)

  • Kai Yuan

    (Central South University
    Central South University
    Central South University
    Central South University)

Abstract

Transposable elements (TEs) through evolutionary exaptation have become an integral part of the human genome, offering ample regulatory sequences and shaping chromatin 3D architecture. While the functional impacts of TE-derived sequences on early embryogenesis have been recognized, their roles in malignancy are only starting to emerge. Here we show that many TEs, especially the pluripotency-related human endogenous retrovirus H (HERVH), are abnormally activated in colorectal cancer (CRC) samples. Transcriptional upregulation of HERVH is associated with mutations of several tumor suppressors, particularly ARID1A. Knockout of ARID1A in CRC cells leads to increased transcription at several HERVH loci, which involves compensatory contribution by ARID1B. Suppression of HERVH in CRC cells and patient-derived organoids impairs tumor growth. Mechanistically, HERVH transcripts colocalize with nuclear BRD4 foci, modulating their dynamics and co-regulating many target genes. Altogether, we uncover a critical role for ARID1A in restraining HERVH, whose abnormal activation can promote tumorigenesis by stimulating BRD4-dependent transcription.

Suggested Citation

  • Chunhong Yu & Xiaoyun Lei & Fang Chen & Song Mao & Lu Lv & Honglu Liu & Xueying Hu & Runhan Wang & Licong Shen & Na Zhang & Yang Meng & Yunfan Shen & Jiale Chen & Pishun Li & Shi Huang & Changwei Lin , 2022. "ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31197-4
    DOI: 10.1038/s41467-022-31197-4
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