Title: Regulation of innate immunity by epigenetic control of endogenous retroelements
Funder: The Academy of Medical Sciences

Abstract: This study aims to test the hypothesis that epigenetic repressors regulate innate immune responses through controlling expression of endogenous retroviruses (ERVs) and transposable elements (collectively termed retroelements). My objective is to use molecular techniques to manipulate repressor proteins in primary immune cells and study effects on the retroelement transcriptome and test whether retroelement expression activates an innate immune responses. Future studies will determine mechanistic details and interrogate these pathways in ex vivo samples from individuals with acute and chronic infections. Ultimately inhibitors of retroelements can be developed to suppress pathological innate immune responses. My PhD thesis demonstrated that viral proteins which degrade certain epigenetic repressors (specifically the human silencing hub, or HUSH complex) activate retroelement expression and enhance anti-viral interferon-stimulated gene (ISG) expression. Other groups recently confirmed my observation that the HUSH complex represses certain retroelements. In parallel emerging literature, retroelements are also associated with pro-inflammatory states in autoimmunity and cancer. These data suggest that the immune system has co-opted mobile retroelements to enhance anti-pathogen defences. However there are very limited studies describing the interplay of ISGs and retroelements in primary immune cells or during infection. I will use lentivector-delivered CRISPR-Cas9 systems to knock-out HUSH complex proteins in primary monocytes derived from healthy human donors. I will seek a role for retroelement expression in normal innate immunity by applying innate ligands, including transfected nucleic acids, to simulate infection in these cells and measure transcriptional changes using RNAseq analyses to define a retroelement signature that associates with ISG responses.

Lay abstract: Approximately one half of the human genome is directly derived from mobile genetic elements including viruses that infected ancestral genomes millions of years ago. This statistic is particularly striking when we consider that only 2-3% of the human genome is constituted of genes that encode proteins. These diverse virus-derived sequences may be collectively referred to as retroelements. Retroelements are remnants of past invaders that have literally assimilated into our genetic code. Most retroelements do not encode proteins but are able to generate nucleic acid products (particularly RNA). The role of retroelements in human health and disease is very poorly understood. During my PhD studies I discovered that retroelements contribute to anti-viral immune defences. This suggests that human cells actively use previous pathogens to enhance defences against new pathogens. These data begin to address the role of this abundant but unexplained genetic code. Preliminary data from my PhD describes how human cells regulate this retroelement defence system through proteins that control the physical and biochemical properties of chromosomes, the structures that carry human genes. This is important new knowledge for human understanding as these defence systems are likely relevant to the consequences of all human infectious diseases, besides contributing to cancer and autoimmune disease (such as lupus and multiple sclerosis). My project will use state-of-the-art molecular biology techniques to further characterise how retroelements contribute to these immune defences in primary human immune cells. In the long-term this understanding may lead to novel diagnostic tests besides generating novel targets for drug treatments.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM