The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

Autor: Liane Fernandes, Annemarthe G. van der Veen, Petra Mlcochova, Christopher H.C. Tie, Ravindra K. Gupta, Helen M. Rowe, Rocio Enriquez-Gasca, James Holt, Kathleen H. Burns, Hale Tunbak, Poppy A Gould, Pierre V. Maillard, Evangelos Giampazolias
Přispěvatelé: Enriquez-Gasca, Rocio [0000-0002-0483-4841], Burns, Kathleen H. [0000-0003-1620-3761], Maillard, Pierre V. [0000-0003-4611-388X], Rowe, Helen M. [0000-0001-5881-0290], Apollo - University of Cambridge Repository, Burns, Kathleen H [0000-0003-1620-3761], Maillard, Pierre V [0000-0003-4611-388X], Rowe, Helen M [0000-0001-5881-0290]
Jazyk: angličtina
Rok vydání: 2020
Předmět:
631/337/1427/2566
0301 basic medicine
Interferon-Induced Helicase
IFIH1
General Physics and Astronomy
DNA damage response
Epigenesis
Genetic
38/1
Gene Knockout Techniques
0302 clinical medicine
Interferon
Receptors
Immunologic
lcsh:Science
Regulation of gene expression
Multidisciplinary
Gene silencing
MDA5
631/208/176/2016
631/67/68/2486
Cell biology
Gene Expression Regulation
Neoplastic
RNA silencing
030220 oncology & carcinogenesis
Interferon Type I
DEAD Box Protein 58
medicine.drug
Signal Transduction
Science
Down-Regulation
Biology
General Biochemistry
Genetics and Molecular Biology
Article
38
38/91
03 medical and health sciences
Cancer epigenetics
38/89
38/44
38/88
medicine
Humans
Epigenetics
RNA
Double-Stranded
Inflammation
631/250/262/2106/2518
Sequence Analysis
RNA
General Chemistry
Phosphoproteins
030104 developmental biology
HEK293 Cells
Long Interspersed Nucleotide Elements
Epigenetic Repression
RIG-I-like receptors
lcsh:Q
Interferon type I
DNA Damage
HeLa Cells
Zdroj: Nature Communications
Nature Communications, Vol 11, Iss 1, Pp 1-15 (2020)
Nature Communications, 11(1). NATURE PORTFOLIO
ISSN: 2041-1723
Popis: Funder: UKRI Future Leaders Fellowship (MR/S034498/1)
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.
Databáze: OpenAIRE
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