Tunbak, H;
Enriquez-Gasca, R;
Tie, CHC;
Gould, PA;
Mlcochova, P;
Gupta, RK;
Fernandes, L;
... Rowe, HM; + view all
(2020)
The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.
Nature Communications
, 11
, Article 5387. 10.1038/s41467-020-19170-5.
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The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s.pdf - Published Version Download (87MB) | Preview |
Abstract
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.
| Type: | Article |
|---|---|
| Title: | The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-020-19170-5 |
| Publisher version: | https://doi.org/10.1038/s41467-020-19170-5 |
| Language: | English |
| Additional information: | 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/. |
| Keywords: | Cancer epigenetics, DNA damage response, Gene silencing, RIG-I-like receptors |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10124217 |
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