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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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Examples of cell type independent, human ES cell and B cell specific Myc targets.(A) Gene expression levels (at log2 scale) of FBL, LIN28 and BLMH in the absence and presence of Myc induction in P493-6 B cells (measured by Affymetrix Exon arrays and Affymetrix U133 Plus 2.0 arrays), and log2 gene expression fold changes between hESC and trophoblasts (measured by Agilent microarrays) are shown. Error bars correspond to standard deviations of replicate samples. (B) ChIP-chip binding signals in human P493-6 B cells and H9 ES cells, and ENCODE ChIP-seq binding signals in three human cancer cell lines. For ChIP-chip, TileMap moving average statistic [62] m was computed for each probe using normalized log2 probe intensities, and 2m was displayed as the intensity measure. For ChIP-seq, a 100 bp sliding window was used to scan the genome. Read count in each window was shown at a 25 bp step size. E-box motifs CACGTG (black) and CANNTG (red) were mapped to peak regions and are also shown. (C) ChIP-chip [34] and ChIP-seq [40] binding signals in mouse ES cells.
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pone-0026057-g005: Examples of cell type independent, human ES cell and B cell specific Myc targets.(A) Gene expression levels (at log2 scale) of FBL, LIN28 and BLMH in the absence and presence of Myc induction in P493-6 B cells (measured by Affymetrix Exon arrays and Affymetrix U133 Plus 2.0 arrays), and log2 gene expression fold changes between hESC and trophoblasts (measured by Agilent microarrays) are shown. Error bars correspond to standard deviations of replicate samples. (B) ChIP-chip binding signals in human P493-6 B cells and H9 ES cells, and ENCODE ChIP-seq binding signals in three human cancer cell lines. For ChIP-chip, TileMap moving average statistic [62] m was computed for each probe using normalized log2 probe intensities, and 2m was displayed as the intensity measure. For ChIP-seq, a 100 bp sliding window was used to scan the genome. Read count in each window was shown at a 25 bp step size. E-box motifs CACGTG (black) and CANNTG (red) were mapped to peak regions and are also shown. (C) ChIP-chip [34] and ChIP-seq [40] binding signals in mouse ES cells.

Mentions: To identify potential Myc direct target genes in hESCs, we performed ChIP-chip in H9 hESCs using one of the anti-Myc antibodies (Santa Cruz) and identified 1787 binding regions within 1984 genes (FDR = 7.16%). The intersection of these Myc-bound hESC targets expressed in undifferentiated hESCs with the Myc direct targets in B cells reveals a common set of 80 up-regulated genes (Figure 4A and Table S3). We selected 11 genes from this set for qPCR validation and in all cases found significant binding to these promoters by Myc (Figure 4B). An example of the expression and Myc ChIP-chip data for the target gene fibrillarin (FBL) common to P493-6 B cells and H9 hESC are shown in Figure 5. Gene ontology analysis using EASE [35] reveals that the set of 80 core up-regulated human Myc targets contains genes involved with ribosome and ribonucleoprotein complex biogenesis, as well as RNA binding and metabolic processes (Figure 4A).


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)

Examples of cell type independent, human ES cell and B cell specific Myc targets.(A) Gene expression levels (at log2 scale) of FBL, LIN28 and BLMH in the absence and presence of Myc induction in P493-6 B cells (measured by Affymetrix Exon arrays and Affymetrix U133 Plus 2.0 arrays), and log2 gene expression fold changes between hESC and trophoblasts (measured by Agilent microarrays) are shown. Error bars correspond to standard deviations of replicate samples. (B) ChIP-chip binding signals in human P493-6 B cells and H9 ES cells, and ENCODE ChIP-seq binding signals in three human cancer cell lines. For ChIP-chip, TileMap moving average statistic [62] m was computed for each probe using normalized log2 probe intensities, and 2m was displayed as the intensity measure. For ChIP-seq, a 100 bp sliding window was used to scan the genome. Read count in each window was shown at a 25 bp step size. E-box motifs CACGTG (black) and CANNTG (red) were mapped to peak regions and are also shown. (C) ChIP-chip [34] and ChIP-seq [40] binding signals in mouse ES cells.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3198433&req=5

pone-0026057-g005: Examples of cell type independent, human ES cell and B cell specific Myc targets.(A) Gene expression levels (at log2 scale) of FBL, LIN28 and BLMH in the absence and presence of Myc induction in P493-6 B cells (measured by Affymetrix Exon arrays and Affymetrix U133 Plus 2.0 arrays), and log2 gene expression fold changes between hESC and trophoblasts (measured by Agilent microarrays) are shown. Error bars correspond to standard deviations of replicate samples. (B) ChIP-chip binding signals in human P493-6 B cells and H9 ES cells, and ENCODE ChIP-seq binding signals in three human cancer cell lines. For ChIP-chip, TileMap moving average statistic [62] m was computed for each probe using normalized log2 probe intensities, and 2m was displayed as the intensity measure. For ChIP-seq, a 100 bp sliding window was used to scan the genome. Read count in each window was shown at a 25 bp step size. E-box motifs CACGTG (black) and CANNTG (red) were mapped to peak regions and are also shown. (C) ChIP-chip [34] and ChIP-seq [40] binding signals in mouse ES cells.
Mentions: To identify potential Myc direct target genes in hESCs, we performed ChIP-chip in H9 hESCs using one of the anti-Myc antibodies (Santa Cruz) and identified 1787 binding regions within 1984 genes (FDR = 7.16%). The intersection of these Myc-bound hESC targets expressed in undifferentiated hESCs with the Myc direct targets in B cells reveals a common set of 80 up-regulated genes (Figure 4A and Table S3). We selected 11 genes from this set for qPCR validation and in all cases found significant binding to these promoters by Myc (Figure 4B). An example of the expression and Myc ChIP-chip data for the target gene fibrillarin (FBL) common to P493-6 B cells and H9 hESC are shown in Figure 5. Gene ontology analysis using EASE [35] reveals that the set of 80 core up-regulated human Myc targets contains genes involved with ribosome and ribonucleoprotein complex biogenesis, as well as RNA binding and metabolic processes (Figure 4A).

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