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.
Highlights
The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of long interspersed element-1s (LINE-1s) elements
We verified by western blot or quantitative reverse transcription PCR (qRT-PCR) that HUSH components were depleted by day 4 post introduction of the shRNAs (Fig. 1b) and found that the IFNstimulated response elements (ISRE)-GFP reporter becomes activated at day 6 post shRNA addition (Fig. 1c)
Combining TASOR and MPP8 depletions revealed that TASOR-depletion could partially inhibit the endogenous IFN-stimulated gene (ISG) response mediated by MPP8-depletion (Fig. 1d)
Summary
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). Recent data have revealed that inactivation of epigenetic silencing, in human cancer cell lines leads to the reactivation of endogenous retroviruses and other TEs8–15 This is accompanied by activation of cytosolic nucleic acid sensors of the innate immune system and production of type I interferons The human silencing hub (HUSH) complex was discovered as a novel epigenetic complex responsible for position-effect variegation of integrated transgenes in human cells[25] It is associated with H3K9me3-dense genomic regions, including the 3 prime ends of zinc finger genes and functions to repress zinc finger genes and ribosomal DNAs25–27. Mutations in MORC2 are associated with neuropathies and these disease mutations have been found to affect MORC2 structure and HUSH function[28]
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