Epigenetic modulation of interferon-stimulated gene expression by the histone chaperone HIRA and the variant histone H3.3

Authors

• M Bachu
• C Chen
• A Narain
• A Nishiyama
• I Zhu
• T Tamura
• H Gosh
• D Landsman
• K Ozato

Abstract

Histone variant H3.3 is implicated in diverse biological processes that involve transcriptional regulation and maintenance of chromatin integrity in embryonic and differentiated cells. In the current study, we examined genome-wide distribution of H3.3 in a steady-state and in response to interferon (IFN) stimulation. Stimulation of bonemarrow-derived-macrophages (BMDMs) and embryonic fibroblasts (MEFs) with IFNgamma or IFNbeta markedly enhanced H3.3 deposition in IFN stimulated genes (ISGs), although IFNs didn’t alter global levels of H3.3 protein. The enrichment of the H3.3 signal was pronounced at the promoter and distal ends of ISGs and strongly correlated with the occupancy of the H3.3 specific chaperone HIRA. Further, these changes coincided with changes in histone modification marks, like H3K4me3, H3K4me1, H3K27Ac, H3K36me3 and that of RNA-Pol II. More importantly, IFN induced H3.3 deposition was strikingly reduced when the Hira gene was conditionally-knocked-out from BMDMs and MEFs, indicating that IFN stimulated H3.3 deposition requires HIRA. Interestingly, transcription of majority of ISGs was greatly upregulated in Hira knockout cells (both BMDM and MEFs). Our results indicate that HIRA is involved in restricting ISG transcription and that initial ISG transcription occurs independent of H3.3 deposition. Based on our RNA-Seq and ChIP-Seq data, we hypothesize that H3.3-HIRA-complex plays a role in maintaining nucleosomal density post-transcription, and further it helps to establish a new epigenetic chromatin state. Our results highlight role of H3.3-HIRA complex in inducible transcription and show that the histone H3.3 occupancy serves as a prolonged epigenetic mark, possibly providing a principal platform for epigenetic memory in innate immunity.

Scientific Focus Area: Immunology

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