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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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Schema of the strategy to identify the MYC core target gene signature.
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pone-0026057-g001: Schema of the strategy to identify the MYC core target gene signature.

Mentions: To identify a species and cell type independent core set of Myc target genes we rigorously re-defined Myc target genes in the P493-6 human B cell model of Burkitt lymphoma containing an inducible MYC transgene [31], [32]. With the ability to regulate Myc expression level, we identified Myc targets by chromatin immunoprecipitation (ChIP) using a promoter array (ChIP-chip), global array-based nuclear run-on assay (ANRO) to measure changes in transcriptional rates [22], and multiple biological replicates for gene expression changes upon Myc induction. Genes that are bound by Myc, responded transcriptionally, and that had significant changes in total mRNA levels are considered direct Myc responsive target genes. With this target gene set in hand, we then identified Myc targets in the human embryonic stem cell line H9 by ChIP-chip and gene expression changes as discussed below. The overall strategy to derive a core set of Myc target genes independent of cell type and species that we designate the Myc Core Signature (MCS), and to identify cell-type specific Myc target genes is depicted in Figure 1 (see Table S1 for data sets analyzed, Table S2 for complete expression and binding analysis, Table S3 for the MCS and cell type specific target lists, and Methods S1 for detailed data analysis procedures).


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)

Schema of the strategy to identify the MYC core target gene signature.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0026057-g001: Schema of the strategy to identify the MYC core target gene signature.
Mentions: To identify a species and cell type independent core set of Myc target genes we rigorously re-defined Myc target genes in the P493-6 human B cell model of Burkitt lymphoma containing an inducible MYC transgene [31], [32]. With the ability to regulate Myc expression level, we identified Myc targets by chromatin immunoprecipitation (ChIP) using a promoter array (ChIP-chip), global array-based nuclear run-on assay (ANRO) to measure changes in transcriptional rates [22], and multiple biological replicates for gene expression changes upon Myc induction. Genes that are bound by Myc, responded transcriptionally, and that had significant changes in total mRNA levels are considered direct Myc responsive target genes. With this target gene set in hand, we then identified Myc targets in the human embryonic stem cell line H9 by ChIP-chip and gene expression changes as discussed below. The overall strategy to derive a core set of Myc target genes independent of cell type and species that we designate the Myc Core Signature (MCS), and to identify cell-type specific Myc target genes is depicted in Figure 1 (see Table S1 for data sets analyzed, Table S2 for complete expression and binding analysis, Table S3 for the MCS and cell type specific target lists, and Methods S1 for detailed data analysis procedures).

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