期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：13
页码：E1587-E1593
DOI：10.1073/pnas.1502461112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceOur study examines an important aspect of adaptive immunity, namely, the process of effector T-cell activation, which leads to the enhanced expression of lineage-specific cytokine genes upon T-cell receptor (TCR) re-engagement. We found that the TNF locus undergoes TCR-induced homologous allelic pairing, which correlates with biallelic expression and requires a molecular motor, myosin VI. Furthermore, we identified a role for myosin VI in mediating the transition of RNA polymerase II (RNAPII) from pausing to productive elongation at cytokine and other related loci. We propose that homologous pairing and RNAPII pause release ensure a rapid and synchronous transcriptional response in effector T cells following antigen re-exposure. 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-, 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.
关键词：homolog pairing ; myosin VI ; polymerase pausing ; GRO-seq
