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Q&A: The HUSH complex – a gatekeeper of type I interferon through epigenetic regulation of LINE-1 elements

Dr Helen Rowe from the Centre for Immunobiology explains how Hale Tunbak and Rocio Enriquez-Gasca in her lab have linked LINE-1 elements and the HUSH complex to regulation of the human innate immune system.

Dr Helen Rowe

Group Leader, Dr Helen Rowe

LINE-1 elements are a class of transposable elements that have amplified their copy number throughout human evolution and now make up around 17 per cent of the human genome. These elements are kept under control early in development to prevent their activity, which could lead to genetic disease. The Rowe Lab, and other labs, have previously identified an epigenetic complex known as the human silencing hub (HUSH) to shutdown LINE-1 expression. Little is known, however, about the impact of HUSH-regulated LINE-1 elements on human health and disease. In this Q&A, Dr Helen Rowe explains how Hale Tunbak and Rocio Enriquez-Gasca in her lab have linked LINE-1 elements and the HUSH complex to regulation of the human innate immune system.

What is new about this study?

In this study, we show that inactivation of the HUSH complex in human primary fibroblasts – connective tissue cells that are involved in wound healing and launching immune responses – results in the activation of interferons and inflammatory genes. This pathway is dependent on expression of LINE-1 elements, which can generate double-stranded RNAs that are sensed by cytoplasmic RIG-I like receptors leading to cells producing type I interferons. Interferons are proteins that boost the immune system through their ability to inhibit viral replication within infected cells, protect uninfected cells from infection and stimulate adaptive antiviral immunity. Finally, we link this new pathway to diverse cancers that are characterised by a common dominant interferon signature, and in which the HUSH complex is notably downregulated.

Is there anything surprising about the results?

LINE-1 elements were recently linked to interferons and inflammation but it was primarily thought that of the 500,000 elements present in the human genome, only a handful that were still mobile could induce interferon production through DNA sensing. Here we find that hundreds of LINE-1 elements represent a natural source of double-stranded RNAs, subject to RNA sensing. These nucleic acids are recognised as foreign by the innate immune system leading to their cytoplasmic detection and signalling of type I interferons leading to induction of interferon response genes. This research, therefore, sheds light on how transposable elements are involved in pathogen defence by the human innate immune system.

Why is the study important?

This research is important because it identifies the HUSH complex as a potential new target for cancer immunotherapy. Interfering with expression of the HUSH complex may make cancers more immunogenic through the release of LINE-1 double-stranded RNAs to induce interferons and potentially increase anti-tumour immunity. Conversely, this research also suggests that release of HUSH-regulated LINE-1 elements may play a causative role in a range of autoimmune and auto-inflammatory diseases. In sum, the HUSH complex and LINE-1 elements may lie at the heart of maintaining the right balance towards immunity rather than autoimmunity.

What are the wider implications?

With this work revealing LINE-1 elements to represent a natural source of double-stranded RNAs under regulation by the HUSH complex, we now hypothesise that this pathway may play a physiological role in normal potentiation of innate immune responses. For example, hundreds of LINE-1 elements may routinely be switched on to act as immune messengers to amplify innate immune sensing upon pathogen challenge. This work, therefore, has broad implications for changing the way we think about how the human immune system works and how it can go wrong in a diverse range of diseases. LINE-1 elements, which are buried within the dark matter of our genome and have been largely unstudied, may in fact represent essential drivers of the mammalian interferon defence system.

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