The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci1. Recent work suggested that rather than up- and downregulating selected groups of genes1,2,3, Myc targets all active promoters and enhancers in the genome (a phenomenon termed ‘invasion’) and acts as a general amplifier of transcription4,5. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B cells and fibroblasts. Consistent with long-standing observations6, we detected general increases in total RNA or messenger RNA copies per cell (hereby termed ‘amplification’)4,5 when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response)7,8 or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, although having the potential to interact with all active or poised regulatory elements in the genome4,5,9,10,11, Myc does not directly act as a global transcriptional amplifier4,5. Instead, our results indicate that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover.

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ChIP-seq, RNA-seq and DNase I-seq experiments have been submitted to the NCBI GEO database with the accession number GSE51011.


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We thank A. Piontini, P. Nicoli, A. Gobbi and M. Capillo for their help with the management of mouse colonies; S. Bianchi, L. Rotta and T. Capra for assistance with the Illumina HiSeq and NanoString platforms; S. Barozzi, A. Oldani and D. Parazzoli for assistance with imaging technologies; S. Bonifacio and G. Diaferia for discussions about DNase I sequencing; and G. Natoli for comments on the manuscript. We are grateful to C.-L. Wei and collaborators (Genome Institute of Singapore) for the sequencing of ChIP-seq samples in a preliminary phase of this study. T.R.K. was supported by the Structured International Post Doc program of the European School of Molecular Medicine. This work was supported by funding from the European Community’s Seventh Framework Programme (FP7/2007-2013), project RADIANT (grant agreement no. 305626) to M.P. and projects EuroSystem (grant agreement no. 200720) and MODHEP (grant agreement no. 259743) to B.A., as well as grants from the European Research Council, the Association for International Cancer Research (AICR), the Italian Health Ministry, Fondazione Cariplo and the Italian Association for Cancer Research (AIRC) to B.A.

Author information

Author notes

    • Arianna Sabò
    • , Theresia R. Kress
    •  & Mattia Pelizzola

    These authors contributed equally to this work.


  1. Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy

    • Arianna Sabò
    • , Theresia R. Kress
    • , Mattia Pelizzola
    • , Stefano de Pretis
    • , Alessandra Tesi
    • , Marco J. Morelli
    • , Pranami Bora
    • , Valerio Bianchi
    • , Alberto Ronchi
    • , Heiko Müller
    • , Stefano Campaner
    •  & Bruno Amati
  2. Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy

    • Arianna Sabò
    • , Theresia R. Kress
    • , Marcin M. Gorski
    • , Mirko Doni
    • , Alessandro Verrecchia
    • , Claudia Tonelli
    • , Giovanni Fagà
    •  & Bruno Amati
  3. Institute of Molecular and Cell Biology, Singapore 138673, Singapore

    • Diana Low
    •  & Ernesto Guccione


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A.S., T.R.K., M.P. and B.A. conceived the work, designed the experiments and interpreted the data. B.A. supervised the project and wrote the manuscript. A.S., T.R.K., M.M.G., A.T., M.D., A.V., C.T., G.F., E.G. and S.C. performed experiments, and M.P., S.d.P., M.J.M., P.B., V.B., A.R., D.L. and H.M. computational data analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Bruno Amati.

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