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

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, Zhuohua Zhang and Kai Yuan ()
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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
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
Zhuohua Zhang: Central South University
Kai Yuan: Central South University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31197-4

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