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Connecting the activities of c-Myc in genome regulation, cellular growth control and oncogenesis

Objective

The c-myc proto-oncogene is a general driving force in cancer. The cmyc product (Myc) is a transcription factor that binds thousands of genomic loci. However, the identity of the Myc-target genes that influence tumor development, as well as the mechanisms through which Myc acts on these genes, remain most elusive questions in the field. We will use next-generation DNA sequencing to create a multi-layered set of genome-wide profiles. We will analyze cultured mouse cells and developing tumors, the latter in a transgenic model of Myc-induced lymphoma. The profiles will include (i.) quantitative mapping of the RNA transcriptome (coding, non-coding and small RNAs), (ii.) protein-DNA interaction profiles, (iii.) epigenome profiling, (iv.) 3D-folding of genomic DNA, (v.) mutational analysis. These datasets will provide broad views and will answer pointed questions about the action of Myc. We will address the hypothesis that many Myc target genes may not be regulated at the level of net mRNA accumulation, but rather of co-transcriptional processing events. We will provide maps for the RNA-Polymerase II complex, transcriptional co-factors and histone-modifying enzymes. We will whether the Myc-binding sites that do not map within promoters may act as enhancers and/or replication origins. We will address the hypothesis that Myc contributes to reprogramming of the genome independently from its localized effects on target genes. We will also ask which genes are targets of mutations and/or epigenetic silencing in Myc-induced lymphoma. High-throughput functional genomics will be used to address which genes suppress or promote Myc-induced lymphoma. Altogether, our data will provide an unprecedented level of insight into Myc function and into the early stages of tumor progression.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/rna
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/clinical medicine/oncology/cancer
  • /natural sciences/biological sciences/genetics and heredity/genome
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

ERC-2010-AdG_20100317
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Funding Scheme

ERC-AG - ERC Advanced Grant

Host institution

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Address
Via Filodrammatici 10
20121 Milano
Italy
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 2 494 000
Principal investigator
Bruno Amati (Dr.)
Administrative Contact
Ilaria Foti (Ms.)

Beneficiaries (1)

ISTITUTO EUROPEO DI ONCOLOGIA SRL
Italy
EU contribution
€ 2 494 000
Address
Via Filodrammatici 10
20121 Milano
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
Principal investigator
Bruno Amati (Dr.)
Administrative Contact
Ilaria Foti (Ms.)