IFN-I
Refactoring the type I interferon locus for functional studies
Type I interferon (IFN-α and IFN-β, collectively referred to as IFN-I) comprises a family of homologous cytokines that signal through the common IFN-I receptor (IFNAR). IFN-I secretion is an essential and universal response to viral infection that induces interferon-inducible genes with diverse antiviral functions. On the other hand, aberrant IFN-I signaling is a prominent feature of multiple autoimmune disease such as systemic lupus erythematosus, suggesting organismal homeostasis requires tight regulation of IFN-I activity. All mammalian IFN-encoding genes comprise a large locus (~350kb in the mouse, ~400kb in humans) that includes Ifnb1 (encoding IFN-β) and two clusters of Ifna genes (encoding IFN-α subtypes) interrupted by a ubiquitously expressed gene Klhl9. Several polymorphisms in the human IFNB1/IFNA locus have been associated in GWAS studies with susceptibility to viral infections or autoimmune disease, yet how these mutations affect IFN-I expression is unclear. Because of the size and unique organization of the locus, several fundamental questions about IFN-I response remain open, such as the role of IFN-α versus IFN-β genes and their regulation by specific cis-regulatory elements. The current project will begin addressing these questions using targeted engineering of the IFN-I locus.
IN COllaboration with:
Boris Reizis, PhD, NYU Langone Health
Nicholas Adams, PhD, NYU Langone Health