ELL facilitates RNA polymerase II pause site entry and release

Byun, Jung S.; Fufa, Temesgen; Wakano, Clay; Fernandez, Alfonso G.; Haggerty, Cynthia M.; Sung, Myong-Hee; Gardner, Kevin

doi:10.1038/ncomms1652

Cited by 44 publications

(46 citation statements)

References 42 publications

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“…For the EGF experiment, cells were treated with EGF (50 ng/ml) for 1 h (41). Cells were treated with nocodazole or olaparib or EGF in 60 mm dishes.…”

Section: Methodsmentioning

confidence: 99%

Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark

Lodhi¹,

Kossenkov²,

Tulin³

2014

Nucleic Acids Research

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Epigenetics are the heritable changes in gene expression or cellular phenotype caused by mechanisms other than changes in the underlying DNA sequence. After mitosis, it is thought that bookmarking transcription factors remain at promoters, regulating which genes become active and which remain silent. Herein, we demonstrate that poly(ADP-ribose)polymerase-1 (PARP-1) is a genome-wide epigenetic memory mark in mitotic chromatin, and we further show that the presence of PARP-1 is absolutely crucial for reactivation of transcription after mitosis. Based on these findings, a novel molecular model of epigenetic memory transmission through the cell cycle is proposed.

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“…For the EGF experiment, cells were treated with EGF (50 ng/ml) for 1 h (41). Cells were treated with nocodazole or olaparib or EGF in 60 mm dishes.…”

Section: Methodsmentioning

confidence: 99%

Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark

Lodhi¹,

Kossenkov²,

Tulin³

2014

Nucleic Acids Research

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“…The molecular mechanism whereby myosin VI regulates transcription during TCR activation remains to be elucidated, but we speculate that myosin VI acts either directly or indirectly to reduce the residence time of RNAPII at pause sites. To date, only a few molecules have been shown to enhance the elongation rate of RNAPII, including human Spt5 homologs and eleven-nineteen lysine-rich leukaemia (ELL) (42)(43)(44). Myosin VI may be part of a larger protein complex, working in conjunction with other factors to stimulate productive elongation.…”

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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“…Finally, we investigated the effect of human AFF4 on the activity of P-TEFb. AFF4 is a subunit of the super elongation complex that is recruited by mixed lineage leukaemia (MLL) proteins to activate the expression of MLL target genes [35][36][37][38] . The N-terminal 300 amino acids of AFF4 were shown to specifically interact with P-TEFb 39,40 .…”

Section: Hiv-1 Tat/tar Does Not Change P-tefb Phosphorylationsmentioning

confidence: 99%

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

2012

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Phosphorylation of RnA polymerase II carboxy-terminal domain (CTD) in hepta-repeats YsPTsPs regulates eukaryotic transcription. Whereas ser5 is phosphorylated in the initiation phase, ser2 phosphorylation marks the elongation state. Here we show that the positive transcription elongation factor P-TEFb is a ser5 CTD kinase that is unable to create ser2/ser5 double phosphorylations, while it exhibits fourfold higher activity on a CTD substrate prephosphorylated at ser7 compared with the consensus hepta-repeat or the YsPTsPK variant. mass spectrometry reveals an equal number of phosphorylations to the number of heptarepeats provided, yet the mechanism of phosphorylation is distributive despite the repetitive nature of the substrate. Inhibition of P-TEFb activity is mediated by two regions in Hexim1 that act synergistically on Cdk9 and Cyclin T1. HIV-1 Tat/TAR abrogates Hexim1 inhibition to stimulate transcription of viral genes but does not change the substrate specificity. Together, these results provide insight into the multifaceted pattern of CTD phosphorylation.

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ELL facilitates RNA polymerase II pause site entry and release

Cited by 44 publications

References 42 publications

Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark

Bookmarking promoters in mitotic chromatin: poly(ADP-ribose)polymerase-1 as an epigenetic mark

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

Serine-7 but not serine-5 phosphorylation primes RNA polymerase II CTD for P-TEFb recognition

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