Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

Aiyar, Sarah E.; Sun, Jian; Blair, Ashley L.; Moskaluk, Christopher A.; Lu, Yun; Ye, Qi Nong; Yamaguchi, Yuki; Mukherjee, Amitava; Ren, Da Ming; Handa, Hiroshi; Li, Rong

doi:10.1101/gad.1214104

Cited by 104 publications

(150 citation statements)

References 64 publications

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“…This study uncovered a fundamental, evolutionarily conserved mechanism that controls TNF␣ transcription in M⌽, which generate a bulk of TNF␣ during inflammatory processes. While many questions regarding the molecular determinants of Pol II stalling remain, this early elongation checkpoint may be subverted in disease, as suggested by recent data linking NELF dysregulation to enhanced cellular proliferation in breast cancer and gastrointestinal adenocarcinomas (39,40). Conceivably, altered NELF levels in M⌽ may lead to an exaggerated inflammatory response or autoimmunity.…”

Section: Discussionmentioning

confidence: 97%

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

Adelman

Kennedy

Nechaev

et al. 2009

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

141

140

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The kinetics and magnitude of cytokine gene expression are tightly regulated to elicit a balanced response to pathogens and result from integrated changes in transcription and mRNA stability. Yet, how a single microbial stimulus induces peak transcription of some genes (TNF␣) within minutes whereas others (IP-10) require hours remains unclear. Here, we dissect activation of several lipopolysaccharide (LPS)-inducible genes in macrophages, an essential cell type mediating inflammatory response in mammals. We show that a key difference between the genes is the step of the transcription cycle at which they are regulated. Specifically, at TNF␣, RNA Polymerase II initiates transcription in resting macrophages, but stalls near the promoter until LPS triggers rapid and transient release of the negative elongation factor (NELF) complex and productive elongation. In contrast, no NELF or polymerase is detectible near the IP-10 promoter before induction, and LPS-dependent polymerase recruitment is rate limiting for transcription. We further demonstrate that this strategy is shared by other immune mediators and is independent of the inducer and signaling pathway responsible for gene activation. Finally, as a striking example of evolutionary conservation, the Drosophila homolog of the TNF␣ gene, eiger, displayed all of the hallmarks of NELF-dependent polymerase stalling. We propose that polymerase stalling ensures the coordinated, timely activation the inflammatory gene expression program from Drosophila to mammals. cytokine gene expression ͉ inflammation ͉ TNF␣ ͉ transcription initiation and elongation ͉ NELF

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Section: Discussionmentioning

confidence: 97%

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

Adelman

Kennedy

Nechaev

et al. 2009

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

141

140

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“…Upon activation by heat shock, Pol II is able to rapidly transcribe these genes. Regulation of Pol II activity after recruitment has also been described in bacteria 23 , yeast 13 and mammalian cell lines 3,[6][7][8][9][10][11][12] , and includes instances where Pol II is found in an inactive pre-initiation complex 24,25 . We will collectively refer to inactive Pol II near the transcription start site as stalled Pol II.…”

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confidence: 95%

RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo

et al. 2007

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It is widely assumed that the key rate-limiting step in gene activation is the recruitment of RNA polymerase II (Pol II) to the core promoter 2 . Although there are well-documented examples where Pol II is recruited to a gene but stalls3 -14, a general role for Pol II stalling in development has not been established. We have performed comprehensive Pol II ChIP-chip assays in Drosophila embryos and identified three distinct Pol II binding behaviors: active (uniform binding across the entire transcription unit), no binding, and stalled (binding at the transcription start site). The striking feature of the ~10% genes that are stalled is that they are highly enriched for developmental control genes that are repressed at the time of analysis or poised for activation during subsequent stages of development. We propose that Pol II stalling facilitates rapid temporal and spatial changes in gene activity during development.Pol II stalling is probably best studied at heat shock genes in Drosophila, where Pol II engages in transcription but pauses immediately downstream of the transcriptional start site 3,4,22 . Upon activation by heat shock, Pol II is able to rapidly transcribe these genes. Regulation of Pol II activity after recruitment has also been described in bacteria 23 , yeast 13 and mammalian cell lines 3,[6][7][8][9][10][11][12] , and includes instances where Pol II is found in an inactive pre-initiation complex 24,25 . We will collectively refer to inactive Pol II near the transcription start site as stalled Pol II.To determine at which genes Pol II stalling occurs during development, we analyzed global Pol II occupancy in whole Drosophila embryos. While this is one of the few systems where The results show that many genes known to be repressed in Toll 10b embryos display strikingly high levels of Pol II near the transcription start site (Fig.1A-D). In some cases the prominent Pol II peak is tightly restricted to the promoter region (e.g. at the tup gene in Fig. 1A), while at other genes Pol II is also found at low levels throughout the transcription unit (e.g. the sog and brk genes Fig. 1C,D). This is consistent with previous evidence that some genes such as sog are transiently activated but then repressed at later stages 26 , while other genes such as tup are never activated in Toll 10b mutants 19,20 .The Pol II profile of repressed genes is clearly distinct from those of active genes ( Fig. 1E, F). For example, the Hbr gene, which encodes an FGF receptor specifically expressed in mesodermal precursors ( Fig. 1E), and ribosomal genes such as RpL3 (Fig.1F), show uniformly high levels of Pol II throughout the transcription unit. Furthermore, genes that are silent in the early embryo simply lack Pol II binding altogether ( Fig. 1G, H). Thus, there appears to be three distinct classes of genes: those with Pol II distributed throughout the transcription unit, those genes with preferential enrichment of Pol II at the transcription site, and genes that lack Pol II binding altogether.To further characterize t...

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“…The mammalian NELF-A gene, also called WHSC2, is a potential contributor to WolfHirschhorn syndrome (Wright et al 1999). The NELF-B subunit, referred to as COfactor of BRCA1 (COBRA-1), interacts with the BRCA-1 protein in a yeast two-hybrid assay and has been reported to bind ER-␣ and AP-1 family members (Ye et al 2001;Aiyar et al 2004;Zhong et al 2004). NELF C/D are translation variants of the same mRNA and are homologous to the mammalian protein TH1-like.…”

mentioning

confidence: 99%

NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly

Gilchrist¹,

Nechaev²,

Lee³

et al. 2008

Genes Dev.

282

298

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The Negative Elongation Factor (NELF) is a transcription regulatory complex that induces stalling of RNA polymerase II (Pol II) during early transcription elongation and represses expression of several genes studied to date, including Drosophila Hsp70, mammalian proto-oncogene junB, and HIV RNA. To determine the full spectrum of NELF target genes in Drosophila, we performed a microarray analysis of S2 cells depleted of NELF and discovered that NELF RNAi affects many rapidly inducible genes involved in cellular responses to stimuli. Surprisingly, only one-third of NELF target genes were, like Hsp70, up-regulated by NELF-depletion, whereas the majority of target genes showed decreased expression levels upon NELF RNAi. Our data reveal that the presence of stalled Pol II at this latter group of genes enhances gene expression by maintaining a permissive chromatin architecture around the promoter-proximal region, and that loss of Pol II stalling at these promoters is accompanied by a significant increase in nucleosome occupancy and a decrease in histone H3 Lys 4 trimethylation. These findings identify a novel, positive role for stalled Pol II in regulating gene expression and suggest that there is a dynamic interplay between stalled Pol II and chromatin structure.[Keywords: Gene expression; transcription elongation; polymerase stalling; chromatin structure] Supplemental material is available at http://www.genesdev.org.

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Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

Cited by 104 publications

References 64 publications

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

Immediate mediators of the inflammatory response are poised for gene activation through RNA polymerase II stalling

RNA polymerase stalling at developmental control genes in the Drosophila melanogaster embryo

NELF-mediated stalling of Pol II can enhance gene expression by blocking promoter-proximal nucleosome assembly

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