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Proc Natl Acad Sci U S A. 2018 Sep 25;115(39):E9162-E9171. doi: 10.1073/pnas.1720930115. Epub 2018 Sep 10.

Interferon stimulation creates chromatin marks and establishes transcriptional memory.

Author information

1
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
2
Laboratory of Biological Chemistry, Department of Chemistry, Faculty of Science, Hokkaido University, 060-0810 Sapporo, Japan.
3
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892.
4
Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University, 606-8507 Kyoto, Japan.
5
Department of Immunology, Yokohama City University Graduate School of Medicine, 236-0004 Yokohama, Japan.
6
DNA Sequencing and Genomics Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; jun.zhu@nih.gov ozatok@nih.gov.
7
Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; jun.zhu@nih.gov ozatok@nih.gov.

Abstract

Epigenetic memory for signal-dependent transcription has remained elusive. So far, the concept of epigenetic memory has been largely limited to cell-autonomous, preprogrammed processes such as development and metabolism. Here we show that IFNβ stimulation creates transcriptional memory in fibroblasts, conferring faster and greater transcription upon restimulation. The memory was inherited through multiple cell divisions and led to improved antiviral protection. Of ∼2,000 IFNβ-stimulated genes (ISGs), about half exhibited memory, which we define as memory ISGs. The rest, designated nonmemory ISGs, did not show memory. Surprisingly, mechanistic analysis showed that IFN memory was not due to enhanced IFN signaling or retention of transcription factors on the ISGs. We demonstrated that this memory was attributed to accelerated recruitment of RNA polymerase II and transcription/chromatin factors, which coincided with acquisition of the histone H3.3 and H3K36me3 chromatin marks on memory ISGs. Similar memory was observed in bone marrow macrophages after IFNγ stimulation, suggesting that IFN stimulation modifies the shape of the innate immune response. Together, external signals can establish epigenetic memory in mammalian cells that imparts lasting adaptive performance upon various somatic cells.

KEYWORDS:

histone H3.3; innate immunity; interferons; memory; transcription

PMID:
30201712
PMCID:
PMC6166839
DOI:
10.1073/pnas.1720930115
[Indexed for MEDLINE]
Free PMC Article

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