Transcriptional Amplification in Tumor Cells with Elevated c-Myc

By Charles Y. Lin, Jakob Lovén, P. Rahl, Ronald M. Paranal, C. Burge, James E. Bradner, Tong Ihn Lee, Richard A. Young. Cell, 2012

1,502 citations recorded by the source corpus.

Summary Elevated expression of the c-Myc transcription factor occurs frequently in human cancers and is associated with tumor aggression and poor clinical outcome. The effect of high levels of c-Myc on global gene regulation is poorly understood, but is widely thought to involve newly activated or repressed “Myc target genes”. We report here that in tumor cells expressing high levels of c-Myc, the transcription factor accumulates in the promoter regions of active genes and causes transcriptional amplification, producing increased levels of transcripts within the cell's gene expression program. Thus, rather than binding and regulating a new set of genes, c-Myc amplifies the output of the existing gene expression program. These results provide an explanation for the diverse effects of oncogenic c-Myc on gene expression in different tumor cells and suggest that transcriptional amplification reduces rate-limiting constraints for tumor cell growth and proliferation.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6738106539191164137cc3371e5a58d9f316c988

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Citations in the corpus

Signal transduction in cancer. (2015, neutral): “Myc can thus serve as a universal amplifier of expressed genes rather than merely binding topromoters and initiating transcriptionde novo (Rahl et al. 2010; Lin et al. 2012; Nie et al. 2012).”
MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “High-quality MYC-binding sites are on the order of 10,000 or more per human genome, although MYC binding does not necessarily correlate with gene expression changes, particularly in systems in which MYC is inducible (Zeller et al. 2006; Kim et al. 2010; Lee et al. 2012; Lin et al. 2012; Nie et al. 2”
Myc and cell cycle control. (2015, background): “Recent reports show that Myc functions as a general amplifier of already active genes butwith low expression levels [95,96].”
MYC activation is a hallmark of cancer initiation and maintenance. (2014, background): “The mechanistic basis for these differences may relate to the recent findings that MYC amplifies the output of previously activated gene expression programs (Lin et al. 2012; Nie et al. 2012; see Levens 2013 and Rahl and Young 2014).”
Selective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers (2013, methodology): “ChIPwas carried out as described in Lin et al. (2012).”
Computational and analytical challenges in single-cell transcriptomics (2015, neutral): “In some contexts, this assumption has been shown to be misleading (for example, upregulation of MYC leads to a two-fold increase in the number of transcripts 52,53 ) but, in general, such approaches are still widely used.”
Selecting between‐sample RNA‐Seq normalization methods from the perspective of their assumptions (2016, background): “For example, a global shift has been observed in DE analysis with low and high c-Myc conditions [19, 20], and this shift was undetected without the use of spike-in controls [23].”
Revisiting Global Gene Expression Analysis (2012, neutral): “…analysis on P493-6 cells expressing low or high levels of c-Myc (Pajic et al., 2000; Schuhmacher et al., 1999) in which cells with high levels of the transcription factor were found to produce 2-to 3-fold higher levels of the same RNA species found in cells with low levels (Lin et al., 2012).”
Pioneer Transcription Factors Target Partial DNA Motifs on Nucleosomes to Initiate Reprogramming (2015, positive): “However, nucleosome-depleted targets were enriched for a less degenerate E-box motif that we and others have previously reported to be associated with c-Myc binding at enhancers (Lin et al., 2012; Nie et al., 2012; Soufi et al., 2012) (Figure 5B, single arrowhead in bottom panel).”
Transcriptional Addiction in Cancer (2017, positive): “MYC can have profound effects because it can function to amplify the entire gene expression program (Figure 4A) (Lin et al., 2012; Nie et al., 2012), and P53 is a powerful tumor suppressor because of its ability to arrest progress through the cell cycle or induce apoptosis (Lane and Levine, 2010).”
MYC, Metabolism, and Cancer. (2015, background): “In addition, high levels of deregulated oncogenic MYC further perturb transcription by invading enhancer sequences, causing nonlinear amplification of target gene expression and supporting constitutive biomass accumulation in cancer cells (48, 53, 54).”