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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.

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Related in: MedlinePlus

Direct Myc target genes in P493-6 B cells defined by ChIP-chip, array-based nuclear run-on, and gene expression changes.Venn diagram illustrating Myc bound target genes identified with Santa Cruz (SC) or Epitomics (Epit) anti-Myc antibodies. Bound genes whose expression changed are indicated for the overlap between SC and Epit. Enriched gene ontologies for these genes are shown.
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pone-0026057-g002: Direct Myc target genes in P493-6 B cells defined by ChIP-chip, array-based nuclear run-on, and gene expression changes.Venn diagram illustrating Myc bound target genes identified with Santa Cruz (SC) or Epitomics (Epit) anti-Myc antibodies. Bound genes whose expression changed are indicated for the overlap between SC and Epit. Enriched gene ontologies for these genes are shown.

Mentions: We combined data derived from Myc ChIP with promoter tiled arrays, genome-wide array-based nuclear run-on to identify transcriptionally regulated genes, and changes in total mRNA levels to rigorously define direct Myc target genes and to exclude those whose expression might be altered at a post-transcription level. To determine the direct binding targets of Myc, ChIP was performed using two different anti-Myc antibodies in human P493-6 B cells, a model of Burkitt lymphoma that have an Epstein-Barr virus genome and a tetracycline (tet)-repressible human MYC transgene. Following removal of tet, Myc protein is highly induced and resting P493-6 cells are recruited into the active cell cycle [31]. Purified ChIP DNA from cells with high Myc levels was amplified and hybridized to Affymetrix human promoter 1.0R arrays. Signals from both Myc IP and IgG controls were normalized, and binding regions were detected and visualized using CisGenome [33]. In these B cells, the Santa Cruz (SC) anti-N-terminal Myc antibody revealed Myc binding to 2357 regions within 2500 genes with a false discovery rate (FDR) of 6.75%, while the Epitomics (Epit) monoclonal anti-N-terminal Myc antibody revealed 2303 bound regions within 2377 genes (FDR = 6.82%). Intersection of these two data sets revealed that Myc binds to the same regions in 1327 genes with two different anti-Myc antibodies (Figure 2).


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)

Direct Myc target genes in P493-6 B cells defined by ChIP-chip, array-based nuclear run-on, and gene expression changes.Venn diagram illustrating Myc bound target genes identified with Santa Cruz (SC) or Epitomics (Epit) anti-Myc antibodies. Bound genes whose expression changed are indicated for the overlap between SC and Epit. Enriched gene ontologies for these genes are shown.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026057-g002: Direct Myc target genes in P493-6 B cells defined by ChIP-chip, array-based nuclear run-on, and gene expression changes.Venn diagram illustrating Myc bound target genes identified with Santa Cruz (SC) or Epitomics (Epit) anti-Myc antibodies. Bound genes whose expression changed are indicated for the overlap between SC and Epit. Enriched gene ontologies for these genes are shown.
Mentions: We combined data derived from Myc ChIP with promoter tiled arrays, genome-wide array-based nuclear run-on to identify transcriptionally regulated genes, and changes in total mRNA levels to rigorously define direct Myc target genes and to exclude those whose expression might be altered at a post-transcription level. To determine the direct binding targets of Myc, ChIP was performed using two different anti-Myc antibodies in human P493-6 B cells, a model of Burkitt lymphoma that have an Epstein-Barr virus genome and a tetracycline (tet)-repressible human MYC transgene. Following removal of tet, Myc protein is highly induced and resting P493-6 cells are recruited into the active cell cycle [31]. Purified ChIP DNA from cells with high Myc levels was amplified and hybridized to Affymetrix human promoter 1.0R arrays. Signals from both Myc IP and IgG controls were normalized, and binding regions were detected and visualized using CisGenome [33]. In these B cells, the Santa Cruz (SC) anti-N-terminal Myc antibody revealed Myc binding to 2357 regions within 2500 genes with a false discovery rate (FDR) of 6.75%, while the Epitomics (Epit) monoclonal anti-N-terminal Myc antibody revealed 2303 bound regions within 2377 genes (FDR = 6.82%). Intersection of these two data sets revealed that Myc binds to the same regions in 1327 genes with two different anti-Myc antibodies (Figure 2).

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