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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.