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Immunity. 2019 Apr 16. pii: S1074-7613(19)30148-7. doi: 10.1016/j.immuni.2019.03.031. [Epub ahead of print]

Natural Genetic Variation Reveals Key Features of Epigenetic and Transcriptional Memory in Virus-Specific CD8 T Cells.

Author information

1
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY, USA.
4
Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
5
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: rudenska@mskcc.org.

Abstract

Stable changes in chromatin states and gene expression in cells of the immune system form the basis for memory of infections and other challenges. Here, we used naturally occurring cis-regulatory variation in wild-derived inbred mouse strains to explore the mechanisms underlying long-lasting versus transient gene regulation in CD8 T cells responding to acute viral infection. Stably responsive DNA elements were characterized by dramatic and congruent chromatin remodeling events affecting multiple neighboring sites and required distinct transcription factor (TF) binding motifs for their accessibility. Specifically, we found that cooperative recruitment of T-box and Runx family transcription factors to shared targets mediated stable chromatin remodeling upon T cell activation. Our observations provide insights into the molecular mechanisms driving virus-specific CD8 T cell responses and suggest a general mechanism for the formation of transcriptional and epigenetic memory applicable to other immune and non-immune cells.

KEYWORDS:

epigenetic; memory; transcription

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