Cellular stresses such as starvation, infection and inflammation trigger autophagy to clear damaged self and foreign materials. Autophagy occurs in conjunction with a global redirection of gene expression that sets a new epigenetic state. Cytokines, particularly interferons (IFNs, type I and type II) strongly induce autophagy in macrophages and dendritic cells. We showed earlier that IFNs induce chromatin exchange in IFN stimulated genes (ISGs), and the core histones are replaced by the variant histone, H3.3
[1]. The H3.3 replacement takes place during ISG transcription elongation, and requires the histone methyltransferase WHSC1 and the chromatin assembly factor HIRA. The H3.3 deposited in the ISGs remains for several cell generations, and forms a lasting epigenetic mark.
We recently noted that stress induced autophagy in macrophages is dependent on and orchestrated by IRF8 [2]. IRF8 led to enhanced transcription of >17 autophagy genes (e.g. Ulk1, Becn1, Atg4d, Atg7, Map1/lc3b, Lamp2, Cst3) that encompassed all steps of autophagy, from initial autophagosome formation to lysosomal fusion to target degradation. Upon infection of bacteria (Listeria) in macrophages, IRF8 directed high, sustained de novo transcription of multiple autophagy genes. Our more recent work shows that IRF8 plays a central role in setting the epigenetic chromatin environment in macrophages and establishes innate immune responses.
