Cell-Type Independent MYC Target Genes Reveal a Primordial Signature Involved in Biomass Accumulation

Hongkai Ji,John L Cleveland,Xiangcan Zhan,Alexandra Nolan,Alexandra Nolan,Mohammad Fallahi,Hoang Mai Doan,Hoang Mai Doan,Jinshui Fan,Jinshui Fan,Cheryl Koh,Cheryl Koh,Christopher Cheadle,Christopher Cheadle,Karen I Zeller,Karen I Zeller,Chi V Dang,George Wu,Angelo De Marzo,Angelo De Marzo,Mikhail V Blagosklonny

doi:10.1371/journal.pone.0026057

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.

Highlights

Key oncogenic pathways are being revealed through sequencing of the human cancer genomes
Identification of direct MYC target genes in a human B cell model of Burkitt lymphoma We combined data derived from Myc chromatin immunoprecipitation (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
Regulation of the Myc Core Signature (MCS) genes involved in nucleolar function and ribosomal biogenesis reveals Myc’s primordial function

Summary

Introduction

Key oncogenic pathways are being revealed through sequencing of the human cancer genomes. While genetic alterations in specific human cancers continue to accumulate through deep sequencing, whether key oncogenic hubs, such as the MYC oncogene, behave in a general way or in a context dependent manner remains poorly understood. Whether alterations in oncogenic transcription factors result in cell-type independent effects has not been fully appreciated. In this regard, we focus on the MYC oncogene, which produces the Myc transcription factor involved in no less than 50% of human cancers, and seek to identify a putative cell-type independent target gene signature that might reveal Myc’s primordial function in metazoans. MYCN is well-known to be amplified in Stage IV neuroblastoma, and children with highly amplified MYCN suffer aggressive, poor prognosis disease [4]

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Results

Conclusion