Limits...
Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation.

Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, Doan HM, Fan J, Cheadle C, Fallahi M, Cleveland JL, Dang CV, Zeller KI - PLoS ONE (2011)

Bottom Line: Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types.Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes.Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. hji@jhsph.edu

ABSTRACT
The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells.

Show MeSH

Related in: MedlinePlus

Correlation of MYC and Myc core target gene signature (MCS) expression among 8129 samples.(A) Correlation plot of MCS versus MYC expression across 8129 samples on the Affymetrix human U133A platform. Correlation coefficient = 0.47. p-value was determined based on correlation between MYC and randomly chosen genes (see Methods S1). Samples from a few cell or tissue types exhibiting patterns of interest are highlighted in color. (B) Correlation plot of MCS versus RXRA expression across 8129 samples on the Affymetrix U133A platform. (C) Total percentage and samples counts of each significantly enriched (FDR<5%) high MYC high MCS cell or tissue type in MYC+ MCS+ samples compared to in all samples. (D) Comparison of total percentage of tumor samples in all of the data (57.7%) to the total percentage of MYC+ MCS+ samples that are tumors (95.9%).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3198433&req=5

pone-0026057-g007: Correlation of MYC and Myc core target gene signature (MCS) expression among 8129 samples.(A) Correlation plot of MCS versus MYC expression across 8129 samples on the Affymetrix human U133A platform. Correlation coefficient = 0.47. p-value was determined based on correlation between MYC and randomly chosen genes (see Methods S1). Samples from a few cell or tissue types exhibiting patterns of interest are highlighted in color. (B) Correlation plot of MCS versus RXRA expression across 8129 samples on the Affymetrix U133A platform. (C) Total percentage and samples counts of each significantly enriched (FDR<5%) high MYC high MCS cell or tissue type in MYC+ MCS+ samples compared to in all samples. (D) Comparison of total percentage of tumor samples in all of the data (57.7%) to the total percentage of MYC+ MCS+ samples that are tumors (95.9%).

Mentions: To further determine the cell-type independence of the MCS, we assessed its expression in a collection of 8129 Affymetrix human U133A microarray samples stored in Gene Expression Omnibus [44], representing about 312 different cell and tissue types. We hypothesized that if the core targets are cell type independent, one should be able to observe a clear correlation between the gene expression level of the MCS and MYC expression across this large collection of microarray samples with different cell types. Intriguingly, we observe a strong and highly statistically significant correlation of MCS expression with MYC (Figure 7A, correlation coefficient = 0.47, p-value<0.001). A small cluster of samples (red circles) enriched in Wilms tumor have low MYC but high MCS for reasons unknown to us (possible explanations include other transcriptional regulators, such as N-Myc, that may activate the same set of genes, lab/batch effects in the microarray experiments, or others). However, other than these samples, the correlation between MYC and MCS are strikingly strong given the heterogeneity of the samples involved in the analysis. Interestingly, when we evaluated the expression of the MCS with that of RXRα, a transcription factor that drives differentiation [45], we observe an inverse correlation (Figure 7B).


Cell-type independent MYC target genes reveal a primordial signature involved in biomass accumulation.

Ji H, Wu G, Zhan X, Nolan A, Koh C, De Marzo A, Doan HM, Fan J, Cheadle C, Fallahi M, Cleveland JL, Dang CV, Zeller KI - PLoS ONE (2011)

Correlation of MYC and Myc core target gene signature (MCS) expression among 8129 samples.(A) Correlation plot of MCS versus MYC expression across 8129 samples on the Affymetrix human U133A platform. Correlation coefficient = 0.47. p-value was determined based on correlation between MYC and randomly chosen genes (see Methods S1). Samples from a few cell or tissue types exhibiting patterns of interest are highlighted in color. (B) Correlation plot of MCS versus RXRA expression across 8129 samples on the Affymetrix U133A platform. (C) Total percentage and samples counts of each significantly enriched (FDR<5%) high MYC high MCS cell or tissue type in MYC+ MCS+ samples compared to in all samples. (D) Comparison of total percentage of tumor samples in all of the data (57.7%) to the total percentage of MYC+ MCS+ samples that are tumors (95.9%).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3198433&req=5

pone-0026057-g007: Correlation of MYC and Myc core target gene signature (MCS) expression among 8129 samples.(A) Correlation plot of MCS versus MYC expression across 8129 samples on the Affymetrix human U133A platform. Correlation coefficient = 0.47. p-value was determined based on correlation between MYC and randomly chosen genes (see Methods S1). Samples from a few cell or tissue types exhibiting patterns of interest are highlighted in color. (B) Correlation plot of MCS versus RXRA expression across 8129 samples on the Affymetrix U133A platform. (C) Total percentage and samples counts of each significantly enriched (FDR<5%) high MYC high MCS cell or tissue type in MYC+ MCS+ samples compared to in all samples. (D) Comparison of total percentage of tumor samples in all of the data (57.7%) to the total percentage of MYC+ MCS+ samples that are tumors (95.9%).
Mentions: To further determine the cell-type independence of the MCS, we assessed its expression in a collection of 8129 Affymetrix human U133A microarray samples stored in Gene Expression Omnibus [44], representing about 312 different cell and tissue types. We hypothesized that if the core targets are cell type independent, one should be able to observe a clear correlation between the gene expression level of the MCS and MYC expression across this large collection of microarray samples with different cell types. Intriguingly, we observe a strong and highly statistically significant correlation of MCS expression with MYC (Figure 7A, correlation coefficient = 0.47, p-value<0.001). A small cluster of samples (red circles) enriched in Wilms tumor have low MYC but high MCS for reasons unknown to us (possible explanations include other transcriptional regulators, such as N-Myc, that may activate the same set of genes, lab/batch effects in the microarray experiments, or others). However, other than these samples, the correlation between MYC and MCS are strikingly strong given the heterogeneity of the samples involved in the analysis. Interestingly, when we evaluated the expression of the MCS with that of RXRα, a transcription factor that drives differentiation [45], we observe an inverse correlation (Figure 7B).

Bottom Line: Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types.Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes.Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America. hji@jhsph.edu

ABSTRACT
The functions of key oncogenic transcription factors independent of context have not been fully delineated despite our richer understanding of the genetic alterations in human cancers. The MYC oncogene, which produces the Myc transcription factor, is frequently altered in human cancer and is a major regulatory hub for many cancers. In this regard, we sought to unravel the primordial signature of Myc function by using high-throughput genomic approaches to identify the cell-type independent core Myc target gene signature. Using a model of human B lymphoma cells bearing inducible MYC, we identified a stringent set of direct Myc target genes via chromatin immunoprecipitation (ChIP), global nuclear run-on assay, and changes in mRNA levels. We also identified direct Myc targets in human embryonic stem cells (ESCs). We further document that a Myc core signature (MCS) set of target genes is shared in mouse and human ESCs as well as in four other human cancer cell types. Remarkably, the expression of the MCS correlates with MYC expression in a cell-type independent manner across 8,129 microarray samples, which include 312 cell and tissue types. Furthermore, the expression of the MCS is elevated in vivo in Eμ-Myc transgenic murine lymphoma cells as compared with premalignant or normal B lymphocytes. Expression of the MCS in human B cell lymphomas, acute leukemia, lung cancers or Ewing sarcomas has the highest correlation with MYC expression. Annotation of this gene signature reveals Myc's primordial function in RNA processing, ribosome biogenesis and biomass accumulation as its key roles in cancer and stem cells.

Show MeSH
Related in: MedlinePlus