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Myosin VI regulates gene pairing and transcriptional pause release in T cells
- Zorca, Cornelia E., Kim, Lark Kyun, Kim, Yoon Jung, Krause, Matthew R., Zenklusen, Daniel, Spilianakis, Charalampos G., Flavell, Richard A.
- Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.13 pp. E1587
- DNA-directed RNA polymerase, T-lymphocytes, adaptive immunity, antigens, genes, loci, myosin, transcription (genetics), tumor necrosis factors
- Naive CD4 T cells differentiate into several effector lineages, which generate a stronger and more rapid response to previously encountered immunological challenges. Although effector function is a key feature of adaptive immunity, the molecular basis of this process is poorly understood. Here, we investigated the spatiotemporal regulation of cytokine gene expression in resting and restimulated effector T helper 1 (Th1) cells. We found that the Lymphotoxin ( LT )/ TNF alleles, which encode TNF-α, were closely juxtaposed shortly after T-cell receptor (TCR) engagement, when transcription factors are limiting. Allelic pairing required a nuclear myosin, myosin VI, which is rapidly recruited to the LT/TNF locus upon restimulation. Furthermore, transcription was paused at the TNF locus and other related genes in resting Th1 cells and released in a myosin VI-dependent manner following activation. We propose that homologous pairing and myosin VI-mediated transcriptional pause release account for the rapid and efficient expression of genes induced by an external stimulus.