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ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription
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 ma...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205910/ https://www.ncbi.nlm.nih.gov/pubmed/35715442 http://dx.doi.org/10.1038/s41467-022-31197-4 |
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author | Yu, Chunhong Lei, Xiaoyun Chen, Fang Mao, Song Lv, Lu Liu, Honglu Hu, Xueying Wang, Runhan Shen, Licong Zhang, Na Meng, Yang Shen, Yunfan Chen, Jiale Li, Pishun Huang, Shi Lin, Changwei Zhang, Zhuohua Yuan, Kai |
author_facet | Yu, Chunhong Lei, Xiaoyun Chen, Fang Mao, Song Lv, Lu Liu, Honglu Hu, Xueying Wang, Runhan Shen, Licong Zhang, Na Meng, Yang Shen, Yunfan Chen, Jiale Li, Pishun Huang, Shi Lin, Changwei Zhang, Zhuohua Yuan, Kai |
author_sort | Yu, Chunhong |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9205910 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92059102022-06-19 ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription Yu, Chunhong Lei, Xiaoyun Chen, Fang Mao, Song Lv, Lu Liu, Honglu Hu, Xueying Wang, Runhan Shen, Licong Zhang, Na Meng, Yang Shen, Yunfan Chen, Jiale Li, Pishun Huang, Shi Lin, Changwei Zhang, Zhuohua Yuan, Kai Nat Commun Article 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. Nature Publishing Group UK 2022-06-17 /pmc/articles/PMC9205910/ /pubmed/35715442 http://dx.doi.org/10.1038/s41467-022-31197-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Yu, Chunhong Lei, Xiaoyun Chen, Fang Mao, Song Lv, Lu Liu, Honglu Hu, Xueying Wang, Runhan Shen, Licong Zhang, Na Meng, Yang Shen, Yunfan Chen, Jiale Li, Pishun Huang, Shi Lin, Changwei Zhang, Zhuohua Yuan, Kai ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title | ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title_full | ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title_fullStr | ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title_full_unstemmed | ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title_short | ARID1A loss derepresses a group of human endogenous retrovirus-H loci to modulate BRD4-dependent transcription |
title_sort | arid1a loss derepresses a group of human endogenous retrovirus-h loci to modulate brd4-dependent transcription |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9205910/ https://www.ncbi.nlm.nih.gov/pubmed/35715442 http://dx.doi.org/10.1038/s41467-022-31197-4 |
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