A Myc Network Accounts for Similarities between Embryonic Stem and Cancer Cell Transcription Programs

c-Myc (Myc) is an important transcriptional regulator in embryonic stem (ES) cells, somatic cell reprogramming, and cancer. Here, we identify a Myc-centered regulatory network in ES cells by combining protein-protein and protein-DNA interaction studies and show that Myc interacts with the NuA4 complex, a regulator of ES cell identity. In combination with regulatory network information, we define three ES cell modules (Core, Polycomb, and Myc) and show that the modules are functionally separable, illustrating that the overall ES cell transcription program is composed of distinct units. With these modules as an analytical tool, we have reassessed the hypothesis linking an ES cell signature with cancer or cancer stem cells. We find that the Myc module, independent of the Core module, is active in various cancers and predicts cancer outcome. The apparent similarity of cancer and ES cell signatures reflects, in large part, the pervasive nature of Myc regulatory networks.

[1]  George Q. Daley,et al.  Reprogramming of human somatic cells to pluripotency with defined factors , 2008, Nature.

[2]  T. Enver,et al.  Forcing cells to change lineages , 2009, Nature.

[3]  T. Golub,et al.  Transformation from committed progenitor to leukaemia stem cell initiated by MLL–AF9 , 2006, Nature.

[4]  M. Cole,et al.  The Essential Cofactor TRRAP Recruits the Histone Acetyltransferase hGCN5 to c-Myc , 2000, Molecular and Cellular Biology.

[5]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[6]  Stuart H. Orkin,et al.  A protein interaction network for pluripotency of embryonic stem cells , 2006, Nature.

[7]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[8]  Jacques Côté,et al.  The highly conserved and multifunctional NuA4 HAT complex. , 2004, Current opinion in genetics & development.

[9]  S. Orkin,et al.  An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells , 2008, Cell.

[10]  Clifford A. Meyer,et al.  Model-based analysis of tiling-arrays for ChIP-chip , 2006, Proceedings of the National Academy of Sciences.

[11]  Patrick Rodriguez,et al.  Efficient biotinylation and single-step purification of tagged transcription factors in mammalian cells and transgenic mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Megan F. Cole,et al.  Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells , 2006, Cell.

[13]  P. Fernandez,et al.  Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation. , 2001, Genes & development.

[14]  Eran Segal,et al.  Stemness, cancer, and cancer stem cells , 2008, Cell cycle.

[15]  Megan F. Cole,et al.  Connecting microRNA Genes to the Core Transcriptional Regulatory Circuitry of Embryonic Stem Cells , 2008, Cell.

[16]  Qikai Xu,et al.  A genome-wide RNAi screen identifies a new transcriptional module required for self-renewal. , 2009, Genes & development.

[17]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[19]  J. Zeitlinger,et al.  Polycomb complexes repress developmental regulators in murine embryonic stem cells , 2006, Nature.

[20]  Shulan Tian,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[21]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[22]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[23]  Clifford A. Meyer,et al.  MYC regulation of a “poor-prognosis” metastatic cancer cell state , 2010, Proceedings of the National Academy of Sciences.

[24]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[25]  Jonghwan Kim,et al.  Mapping DNA-protein interactions in large genomes by sequence tag analysis of genomic enrichment , 2005, Nature Methods.

[26]  B. Panning,et al.  An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity , 2008, Cell.

[27]  Jun Qin,et al.  Involvement of the TIP60 Histone Acetylase Complex in DNA Repair and Apoptosis , 2000, Cell.

[28]  M. Cole,et al.  25 years of the c-Myc oncogene. , 2006, Seminars in cancer biology.

[29]  A. Nobel,et al.  The molecular portraits of breast tumors are conserved across microarray platforms , 2006, BMC Genomics.

[30]  Howard Y. Chang,et al.  Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. , 2009, Cell stem cell.

[31]  Jonghwan Kim,et al.  Use of in vivo biotinylation to study protein–protein and protein–DNA interactions in mouse embryonic stem cells , 2009, Nature Protocols.

[32]  P. Greengard,et al.  Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor , 2004, Nature Medicine.

[33]  M. Clarke,et al.  Stem Cells and Cancer: Two Faces of Eve , 2006, Cell.

[34]  Wenjun Guo,et al.  Induction of pluripotent stem cells by defined factors is greatly improved by small-molecule compounds , 2008, Nature Biotechnology.

[35]  Guo-Cheng Yuan,et al.  EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. , 2008, Molecular cell.

[36]  S. Yamanaka,et al.  Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors , 2006, Cell.

[37]  Mike J. Mason,et al.  Role of the Murine Reprogramming Factors in the Induction of Pluripotency , 2009, Cell.

[38]  Herbert Schulz,et al.  A genome-scale RNAi screen for Oct4 modulators defines a role of the Paf1 complex for embryonic stem cell identity. , 2009, Cell stem cell.

[39]  Shridar Ganesan,et al.  X chromosomal abnormalities in basal-like human breast cancer. , 2006, Cancer cell.

[40]  B. Paw,et al.  Identification of ZBP-89 as a Novel GATA-1-Associated Transcription Factor Involved in Megakaryocytic and Erythroid Development , 2008, Molecular and Cellular Biology.

[41]  Carlos Cordon-Cardo,et al.  Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  I. Weissman,et al.  Stem cells, cancer, and cancer stem cells , 2001, Nature.

[43]  N. D. Clarke,et al.  Integration of External Signaling Pathways with the Core Transcriptional Network in Embryonic Stem Cells , 2008, Cell.

[44]  J. Utikal,et al.  Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution. , 2007, Cell stem cell.

[45]  Jeffrey T. Chang,et al.  Oncogenic pathway signatures in human cancers as a guide to targeted therapies , 2006, Nature.

[46]  Lisa E. Gralinski,et al.  Transcriptional Regulation of the mdm2 Oncogene by p53 Requires TRRAP Acetyltransferase Complexes , 2002, Molecular and Cellular Biology.

[47]  Megan F. Cole,et al.  Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells , 2005, Cell.

[48]  Jill D. Gerber,et al.  The p400 Complex Is an Essential E1A Transformation Target , 2001, Cell.

[49]  Pablo Tamayo,et al.  Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Robert L. Judson,et al.  Opposing microRNA families regulate self-renewal in mouse embryonic stem cells , 2010, Nature.

[51]  Victor X Jin,et al.  A comprehensive ChIP-chip analysis of E2F1, E2F4, and E2F6 in normal and tumor cells reveals interchangeable roles of E2F family members. , 2007, Genome research.

[52]  R. Stewart,et al.  Induced Pluripotent Stem Cell Lines Derived from Human Somatic Cells , 2007, Science.

[53]  Mark J. Murphy,et al.  Pbx1 regulates self-renewal of long-term hematopoietic stem cells by maintaining their quiescence. , 2008, Cell stem cell.

[54]  T. Misteli,et al.  Hyperdynamic plasticity of chromatin proteins in pluripotent embryonic stem cells. , 2006, Developmental cell.

[55]  A. Shakya,et al.  Stem cells, stress, metabolism and cancer: a drama in two Octs. , 2009, Trends in biochemical sciences.

[56]  D. Livingston,et al.  MYC recruits the TIP60 histone acetyltransferase complex to chromatin , 2003, EMBO reports.

[57]  Eran Segal,et al.  Module map of stem cell genes guides creation of epithelial cancer stem cells. , 2008, Cell stem cell.

[58]  M. Cole,et al.  The Novel ATM-Related Protein TRRAP Is an Essential Cofactor for the c-Myc and E2F Oncoproteins , 1998, Cell.

[59]  X. Chen,et al.  The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells , 2006, Nature Genetics.

[60]  B. Klein,et al.  Embryonic stem cell markers expression in cancers. , 2009, Biochemical and biophysical research communications.

[61]  T. Parmely,et al.  Identification of New Subunits of the Multiprotein Mammalian TRRAP/TIP60-containing Histone Acetyltransferase Complex* , 2003, Journal of Biological Chemistry.