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-γ 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.

Epigenetic signals that direct cell type specific interferon beta response in mouse cells

“…The latter process might be related to the loss of long-range interactions observed during induction of differentiation in mouse ESCs (Feldmann et al, 2020). Furthermore, a recent study describes the reorganization of the 3D genome around ISG loci upon both IFNβ and IFNγ treatment, which involves loop formation, nucleosome remodeling and an increase of DNA accessibility (Platanitis et al, 2021). Thus, it is emerging that a reorganization of long-range chromatin interactions represents an important part of IFN mediated gene induction.…”