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The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609715/ https://www.ncbi.nlm.nih.gov/pubmed/33144593 http://dx.doi.org/10.1038/s41467-020-19170-5 |
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author | Tunbak, Hale Enriquez-Gasca, Rocio Tie, Christopher H. C. Gould, Poppy A. Mlcochova, Petra Gupta, Ravindra K. Fernandes, Liane Holt, James van der Veen, Annemarthe G. Giampazolias, Evangelos Burns, Kathleen H. Maillard, Pierre V. Rowe, Helen M. |
author_facet | Tunbak, Hale Enriquez-Gasca, Rocio Tie, Christopher H. C. Gould, Poppy A. Mlcochova, Petra Gupta, Ravindra K. Fernandes, Liane Holt, James van der Veen, Annemarthe G. Giampazolias, Evangelos Burns, Kathleen H. Maillard, Pierre V. Rowe, Helen M. |
author_sort | Tunbak, Hale |
collection | PubMed |
description | The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex. |
format | Online Article Text |
id | pubmed-7609715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76097152020-11-10 The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s Tunbak, Hale Enriquez-Gasca, Rocio Tie, Christopher H. C. Gould, Poppy A. Mlcochova, Petra Gupta, Ravindra K. Fernandes, Liane Holt, James van der Veen, Annemarthe G. Giampazolias, Evangelos Burns, Kathleen H. Maillard, Pierre V. Rowe, Helen M. Nat Commun Article The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex. Nature Publishing Group UK 2020-11-03 /pmc/articles/PMC7609715/ /pubmed/33144593 http://dx.doi.org/10.1038/s41467-020-19170-5 Text en © The Author(s) 2020 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 Tunbak, Hale Enriquez-Gasca, Rocio Tie, Christopher H. C. Gould, Poppy A. Mlcochova, Petra Gupta, Ravindra K. Fernandes, Liane Holt, James van der Veen, Annemarthe G. Giampazolias, Evangelos Burns, Kathleen H. Maillard, Pierre V. Rowe, Helen M. The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title_full | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title_fullStr | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title_full_unstemmed | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title_short | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
title_sort | hush complex is a gatekeeper of type i interferon through epigenetic regulation of line-1s |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609715/ https://www.ncbi.nlm.nih.gov/pubmed/33144593 http://dx.doi.org/10.1038/s41467-020-19170-5 |
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