Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

Aiyar, Sarah E.; Blair, Ashley L.; Hopkinson, D. A.; Bekiranov, Stefan; Li, Rong

doi:10.1038/sj.onc.1210047

Cited by 21 publications

(28 citation statements)

References 68 publications

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“…5, 6). Although our work is the first to investigate the mechanisms of NELF's positive effects on gene expression, we note that previous microarray analyses of NELF-depleted human cells also detected significant numbers of transcripts that were down-regulated upon NELF depletion (Aiyar et al 2007;Narita et al 2007).…”

Section: Identification Of Nelf Target Genesmentioning

confidence: 76%

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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Section: Identification Of Nelf Target Genesmentioning

confidence: 76%

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

View full text Add to dashboard Cite

show abstract

“…Several recent gene level expression profiling studies in HeLa cells and Drosophila S2 cells have uncovered a number of interesting in vivo functions of NELF that might not have been predicted based on its in vitro biochemical properties (20,23,32). For example, Handa and co-workers (23) showed that human NELF mediated the 3Ј end processing of replicationdependent histone genes, the transcripts of which normally end with a stem-loop rather than polyadenylated tail.…”

Section: Discussionmentioning

confidence: 99%

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

Sun

2010

Journal of Biological Chemistry

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The human negative elongation factor (NELF) is a four-subunit protein complex that inhibits the movement of RNA polymerase II (RNAPII) at an early elongation stage in vitro. NELFmediated stalling of RNAPII also attenuates transcription of a number of inducible genes in human cells. To obtain a genomewide understanding of human NELF-mediated transcriptional regulation in vivo, we carried out an exon array study in T47D breast cancer cells with transient small interfering RNA knockdown of individual NELF subunits. Upon depletion of NELF-A, -C, or -E, the vast majority of NELF-regulated genes were downregulated. Many of the down-regulated genes encode proteins that play key roles in cell cycle progression. Consequently, NELF knockdown resulted in significant reduction in DNA synthesis and cell proliferation. Chromatin immunoprecipitation showed that NELF knockdown led to dissociation of RNAPII from the promoter-proximal region of the cell cycle-regulating genes. This was accompanied by decreased histone modifications associated with active transcription initiation (H3K9Ac) and elongation (H3K36Me3), as well as reduced recruitment of the general transcription factor TFIIB and increased overall histone occupancy at a subset of the down-regulated promoters. Lastly, our study indicates that NELF regulates alternative transcription initiation of BSG (Basigin) gene by differentially influencing RNAPII density at the two neighboring exons at the 5 end of the gene. Taken together, our data suggest a diverse transcriptional consequence of NELF-mediated RNAPII pausing in the human genome.

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“…Several researchers have reported that TFF1 was a downstream target to COBRA1 in breast cancer and UG-C [9,11,22] . By testing the mRNA levels of TFF1 in HCC cell lines, we attempted to elucidate the correlation between COBRA1 and TFF1 in HCC.…”

Section: Mrna Expression Levels Of Tff1 In Different Cell Linesmentioning

confidence: 99%

“…A number of researchers have proposed that TFF1 is a tumor suppressor gene [11,20] . Aiyar et al identified TFF1 as one of the genes that is regulated by COBRA1 in breast cancer [9] . COBRA1 regulates a number of clustered genes (including TFF1) and its deregulated expression has been reported in various types of cancers [8,9,11,21,22] .…”

Section: Introductionmentioning

confidence: 99%

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The potential involvement of the cofactor of BRCA1 in hepatocellular carcinoma pathogenesis

et al. 2016

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<p>The cofactor of BRCA1 (COBRA1), which also refers to negative elongation factor polypeptide B (NELF-B), is a negative elongation factor (NELF) subunit that has been implicated in the development and progression of several cancers. While reduced COBRA1 expression has been associated with metastatic breast cancer, COBRA1 negatively regulates the activator protein-1 (AP-1) complex, leading to the down-regulation of trefoil factor-1 (TFF1) expression in gastric cancer cell lines. The involvement of COBRA1 in hepatocellular carcinoma (HCC) tumor formation and progression is not known. Here, we investigated the expression of COBRA1, the AP-1 complex, and TFF1 in several HCC cell lines; ranging from low- to high-grade HCC cell lines generated from patients with different stages of the disease. Our results showed that the COBRA1 protein was highly expressed in the low-grade HCC cell line, while significantly down-regulated in high-grade HCC cell lines. TFF1, previously regarded as a COBRA1 target gene, was only expressed in the low-grade HCC cell line and the control cells. Our results suggest that COBRA1 may play a role in HCC pathogenesis and progression. The TFF1 mRNA expression profile was uncorrelated to that of the AP-1 complex subunit proteins, which suggests the involvement of other regulatory pathways in TFF1 expression; however, this requires further study.</p>

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Regulation of clustered gene expression by cofactor of BRCA1 (COBRA1) in breast cancer cells

Cited by 21 publications

References 68 publications

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

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

Human Negative Elongation Factor Activates Transcription and Regulates Alternative Transcription Initiation

The potential involvement of the cofactor of BRCA1 in hepatocellular carcinoma pathogenesis

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