The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s
Authors
Tunbak, Hale
Tie, Christopher H. C.
Gould, Poppy A.
Mlcochova, Petra
Gupta, Ravindra K.
Fernandes, Liane
Holt, James
van der Veen, Annemarthe G.
Giampazolias, Evangelos
Publication Date
2020-11-03Journal Title
Nature Communications
Publisher
Nature Publishing Group UK
Volume
11
Issue
1
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Tunbak, H., Enriquez-Gasca, R., Tie, C. H. C., Gould, P. A., Mlcochova, P., Gupta, R. K., Fernandes, L., et al. (2020). The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s. Nature Communications, 11 (1) https://doi.org/10.1038/s41467-020-19170-5
Description
Funder: UKRI Future Leaders Fellowship (MR/S034498/1)
Abstract
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.
Keywords
Article, /631/67/68/2486, /631/208/176/2016, /631/250/262/2106/2518, /631/337/1427/2566, /38, /38/44, /38/89, /38/91, /38/88, /38/1, article
Sponsorship
Wellcome Trust (Wellcome) (101200/Z/13/Z, WT108082AIA, WT108082AIA, 101200/Z/13/Z, 101200/Z/13/Z)
EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (678350, 678350, 678350, 678350)
Rosetrees Trust (A2630)
Identifiers
s41467-020-19170-5, 19170
External DOI: https://doi.org/10.1038/s41467-020-19170-5
This record's URL: https://www.repository.cam.ac.uk/handle/1810/329475
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.