Stable Pausing by RNA Polymerase II Provides an Opportunity to Target and Integrate Regulatory Signals

Henriques, Telmo; Gilchrist, Daniel A.; Nechaev, Sergei; Bern, Michael D.; Muse, Ginger W.; Burkholder, Adam; Fargo, David C.; Adelman, Karen

doi:10.1016/j.molcel.2013.10.001

Cited by 227 publications

(319 citation statements)

References 46 publications

(77 reference statements)

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“…Precisely how these two processes are interconnected remains to be elucidated until a live-cell imaging approach becomes available. Nevertheless, subnuclear localization and RNAPII pausing are emerging as critical regulatory events (18,35,(47)(48)(49), which play a role in regulating a multitude of cellular responses. experiments.…”

Section: Discussionmentioning

confidence: 99%

Myosin VI regulates gene pairing and transcriptional pause release in T cells

Zorca¹,

Kim

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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.+ T cells have the potential to differentiate into several effector lineages (1), which play distinct roles in adaptive immune responses (2, 3). The polarization process is driven by many well-characterized transcription factors and epigenetic modifications. For instance, following T-cell receptor (TCR) and cytokine-mediated activation, naive CD4 + T cells transcribe low levels of the alternatively expressed genes IFN-γ and IL-4, IL-5, and IL-13, irrespective of their ultimate effector lineage fate (4). During differentiation, however, contrasting activation patterns are established: T helper 1 (Th1) cells exclusively express the signature cytokine interferon-gamma (IFN-γ) in a T-bet-dependent manner, whereas Th2 cells exclusively express IL-4, IL-5, and IL-13 in a Gata3-dependent manner. These changes in transcriptional activity have been demonstrated by the appearance of DNase I hypersensitive sites, as well as by changes in histone acetylation and DNA methylation patterns (5-8). Furthermore, recent work has demonstrated that interchromosomal associations between cytokine genes play an important role in the differentiation process (9, 10). Overall, a vast array of transcription factors, epigenetic modifications, and long-range interactions are needed to establish the identity of effector Th cells. An important aspect of effector T-cell function is the rapid and efficient induction of cytokine gene expression upon antigen encounter. However, the precise spatial and temporal aspects of effector T-cell transcriptional activation are still largely unknown.A fundamental feature of genome regulation is the spatial organization of genes into chromosomal territories. Although chromosomes occupy distinct territories in the nucleus, their location is cell type-specific and may change upon cellular activation. Notably, cell activation has been shown to promote extensive intermingling among chromosomal territories (11,12). In addition, the position of individual gene...

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Section: Discussionmentioning

confidence: 99%

Myosin VI regulates gene pairing and transcriptional pause release in T cells

Zorca¹,

Kim

Kim³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…To identify S and potential AS transcription start sites (tss), we remapped publicly available short-capped RNA highthroughput sequencing datasets (Nechaev et al 2010;Henriques et al 2013) and filtered to isolate only nonunique reads. Potential S and AS tss were observed for all three LTR retroTns (Figure 1, B-D, blue).…”

Section: Ltr Retrotn As Transcription Initiates From Within or Near Ltrsmentioning

confidence: 99%

Antisense Transcription of Retrotransposons in Drosophila: An Origin of Endogenous Small Interfering RNA Precursors

2015

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Movement of transposons causes insertions, deletions, and chromosomal rearrangements potentially leading to premature lethality in Drosophila melanogaster. To repress these elements and combat genomic instability, eukaryotes have evolved several small RNA-mediated defense mechanisms. Specifically, in Drosophila somatic cells, endogenous small interfering (esi)RNAs suppress retrotransposon mobility. EsiRNAs are produced by Dicer-2 processing of double-stranded RNA precursors, yet the origins of these precursors are unknown. We show that most transposon families are transcribed in both the sense (S) and antisense (AS) direction in Dmel-2 cells. LTR retrotransposons Dm297, mdg1, and blood, and non-LTR retrotransposons juan and jockey transcripts, are generated from intraelement transcription start sites with canonical RNA polymerase II promoters. We also determined that retrotransposon antisense transcripts are less polyadenylated than sense. RNA-seq and small RNA-seq revealed that Dicer-2 RNA interference (RNAi) depletion causes a decrease in the number of esiRNAs mapping to retrotransposons and an increase in expression of both S and AS retrotransposon transcripts. These data support a model in which double-stranded RNA precursors are derived from convergent transcription and processed by Dicer-2 into esiRNAs that silence both sense and antisense retrotransposon transcripts. Reduction of sense retrotransposon transcripts potentially lowers element-specific protein levels to prevent transposition. This mechanism preserves genomic integrity and is especially important for Drosophila fitness because mobile genetic elements are highly active.

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“…[92][93][94][95][96][97][98] This abundance of binding is thought to reflect the fact that Pol II quickly transitions from the pre-initiation complex (PIC) to the paused state at most genes, 99 and can be stably positioned at paused sites for several minutes prior to productive elongation. 96,[98][99][100][101][102] Thus, as opposed to yeast systems, the transition between transcription initiation and productive elongation is regulated in higher metazoans. While there are many ideas about the purpose of Pol II pausing, it is clear that regulating polymerase elongation allows fine-tuning of gene expression (for a discussion about proposed functions of pausing see refs.…”

Section: Pol II Elongation Control: a Cdk-9-mediated Transition In Mementioning

confidence: 99%