Program > Browse abstracts by author > Maillard Pierre

Transposable Elements (TEs) constitute both a potential threat to genome integrity and a ready source of genetic material for co-option. In development, TEs are subject to epigenetic silencing through TRIM28, KRAB-zinc finger proteins and the Human Silencing Hub (HUSH) complex. We recently showed that the HUSH complex is an epigenetic regulator of Long INterspersed Element-1s (LINE1s) and long terminal repeats (LTRs) and regulates the type I interferon (IFN) response in adult tissues. Inactivation of this complex leads to the cytoplasmic accumulation of LINE1 RNAs; a double-stranded RNA (dsRNA)-sensing dependent IFN response; and induction of IFN-stimulated genes (ISGs).

Human induced pluripotent stem cells (iPSCs) are canonically insensitive to IFNs. Instead showing intrinsic expression of a subset of ISGs and anti-viral RNAi. These cells show increased expression of LINE1 mRNA. Based on this, we hypothesise that components of the type I IFN induction pathway are epigenetically repressed in pluripotent stem cells to protect from fatal interactions caused by retroelement-mediated induction of type I IFN. We use an isogenic IPSC and NPC comparison model to identify changes in IFN regulation between IFN sensitive and insensitive cells.

Our data suggest that human iPSCs are mildly responsive to the dsRNA analogue, Poly(I:C), with upregulation of some ISGs. Depletion of MPP8, a component of the HUSH complex, also leads to partial ISG upregulation, which appears to act independently of both the type I IFN receptor (IFNAR) and of downstream JAK STAT signalling. By integrating RNA sequencing and chromatin profiling data, we are assessing how type I IFN is regulated in early development. This work aims to illuminate how cells may transition to a state of immune evasion.