Interferons Reshape the 3D Conformation and Accessibility of Macrophage Chromatin

Abstract

Engagement of macrophages in innate immune responses is directed and enhanced by type I and type II interferons. An essential component of IFN activity is the use of JAK-STAT signal transduction for the transcriptional control of interferon-stimulated genes (ISG). Here, we study the immediate early nuclear response to type I IFN and IFN-{gamma} in murine macrophages. Despite their distinct immunological activities, both IFN types triggered highly overlapping epigenomic and transcriptional changes. These changes included a rapid rearrangement of the 3D chromatin organization and an increase of DNA accessibility at ISG loci. ISGF3, the major transcriptional regulator of ISG, controlled homeostatic as well as induced-state DNA accessibility at a subset of ISG. Increases in DNA accessibility correlated with the appearance of activating histone marks at surrounding nucleosomes. Collectively our data emphasize changes in the three-dimensional nuclear space and epigenome as an important facet of transcriptional control by the IFN-induced JAK-STAT pathway.