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MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis (RNA-Seq)

ABSTRACT: MYC is a potent oncogene associated with aggressive disease in many distinct tumor types. Transforming members of the MYC family (MYC, MYCL1, MYCN) encode transcription factors containing six highly conserved regions, termed MYC homology Boxes (MBs). Here, we conduct proteomic profiling of the MB interactomes, demonstrating that half of MYC interactors require one or more MBs for binding. Comprehensive phenotypic analyses revealed that two MBs are universally required for transformation. MBII interaction with acetyltransferase-containing complexes results in histone hyperacetylation and is essential for MYC-dependent tumor initiation. By contrast, MB0 interacts with transcription elongation factors through direct binding to the general transcription factor TFIIF, and deletion of MB0 severely inhibits tumor growth but is dispensable for tumor initiation. Notably, the full transforming activity of MYC can be restored upon co-expression of MB0 and MBII deletion mutants, indicating that these two regions confer unique biological functions, each required for oncogenic MYC activity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE117407 | GEO | 2018/11/08

REPOSITORIES: GEO

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Project description:Medulloblastoma (MB) is the most common malignant brain tumor. MB is a cerebellar tumor that occurs mostly in children between the ages of 3-7 years but also in adults. Human MBs are classified into four subgroups: Wingless (WNT), Sonic Hedgehog (SHH), Group 3 (G3) and G4, each of which with distinct molecular signatures. SHH MBs with MYCN amplification and TP53 mutations and G3 MBs characterized by C-MYC (MYC) overexpression in ~17% of cases from gene amplification with stem like properties, are the most aggressive and least curable with current therapeutic regimen. Using an orthotopic transplant approach, we found that enforced expression of MYCN in cerebellar granule neural progenitors (CGNPs) from 5-7 days old Trp53-null mice induced SHH MBs after transfer in the cortices or cerebella of naive recipient mice. In contrast, overexpression of MYC induced G3 MBs. Because MYCN and MYC bind to the same E-box DNA sequences, we hypothesized that the difference between MYC and MYCN-induced gene expression and tumor identity might be due to their interaction with different partners in CGNPs. In this study, we investigated the role of the Myc interacting zinc finger protein 1 (MIZ1). We found that MIZ1 binds with higher affinity to MYC than to MYCN and that MIZ1 and MYC co-occupy thousands of promoters in G3 MB. Remarkably, enforced expression of a MYC mutant (MYCV394D) that no longer binds to MIZ1 in Trp53-null CGNPs or expression of wild type MYC in CGNPs that lack functional Miz1 resulted in massive changes of the resulting tumorâ??s transcriptional program. Tumors differed from both SHH and G3 medulloblastoma and had a later time of onset compared to MYC-driven G3 medulloblastoma. Our data demonstrate that interaction of MYC with MIZ1 is required for the development of G3 medulloblastoma. ChIP-Seq experiments for Miz1, c-Myc and NMyc from murine medulloblastoma material. Either sorted tumor cells (Miz1 and c-Myc) or spheres from tumor cells (Miz1 and NMyc) were used. Input-samples were sequenced as controls. RNA-Seq from G3 medulloblastomas after restoration of Atoh1 expression.

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MYC protein interactome profiling reveals functionally distinct regions that cooperate to drive tumorigenesis (RNA-Seq)

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