Unknown,Transcriptomics,Genomics,Proteomics

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Elevated expression of the H3K36me2 demethylase Kdm8/Jmjd5, a direct Miz1 target gene causes prolonged postnatal Schwann cell proliferation in the murine Miz1∆POZ neuropathy

ABSTRACT: The deletion of the POZ domain of the transcription factor Miz1 leads to a late onset neuropathy with subsequent spontaneous regeneration in mice. In this study, we aim to identify genes that are involved in the development of this neuropathy. We traced first gene regulatory changes in sciatic nerve tissue from Miz1∆POZ mice to 30 days after birth. At this time point, we harvested samples of sciatic nerve tissue from several mice and performed RNAseq analysis to identify differentially expressed genes between Miz1∆POZ and wild type mice.

INSTRUMENT(S): Illumina HiSeq 1500

ORGANISM(S): Mus musculus

SUBMITTER: Marco Mernberger

PROVIDER: E-MTAB-5600 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Medulloblastomas (MBs) are cerebellar tumors that can be classified into molecularly distinct subgroups that differ in pathology and prognosis. The mechanisms that underlie subgroup specification are largely unknown. While human SHH MBs express MYCN, Group3 (G3) MBs are associated with c-MYC (MYC) overexpression and often show metastasis that confers a poor prognosis. Although MYC proteins are thought to be functionally exchangeable, ectopic expression of Myc or N-myc in Trp53-/-;Cdkn2c-/- cerebellar granule neuron progenitors (GNPs) induces G3 and SHH MBs, respectively, demonstrating that each Myc protein has distinct biological properties. We now show that Myc and N-myc differ in their affinity to Miz1 and that Myc, but not N-myc, effectively recruits Miz1 to its target sites on chromatin. The interaction of Myc with Miz1 is required for the genesis of G3 MB. Myc suppresses ciliogenesis and âreprogramsâ the transcriptome of SHH-dependent GNPs to stem-like cells by repressing genes highly expressed in SHH MB via Miz1. Consistently, target genes of Myc/Miz1 are repressed in human G3 MBs but not in other MB subgroups. Collectively, the data show that the interaction of Myc with Miz1 is a defining hallmark of G3 MB development. In this study, we show that Myc and N-myc differ in their affinity for Miz1, and Myc/Miz1 interaction is required for Group3 medulloblastoma (MB). The gene expression profiles of these tumors were compared to our previously published Group3 MB model as well as SHH model of MB (Kawachi et al., 2012, Cancer Cell). Cerebellar granule neuron progenitors (GNPs) [dka220-222] from postnatal (P) 6 Math1-GFP;Trp53-/-;Cdkn2c-/-. For SHH medulloblastomas, [dka204-206] and [blm015-017 or dka050-dka051], spontaneous medulloblastomas from Cdkn2c-/-;Trp53Fl/Fl;Nestin-Cre (Kawachi et al., 2012, Cancer Cell) and Ptch1+/-;Cdkn2c-/- (Uziel et al., 2005, Genes Dev) were used, respectively. Myc- [dka201-203] and MycV394D (termed MycVD thereafter)- [bvo017-bvo023] tumors were from Trp53-/-;Cdkn2c-/- cerebella of P6-P7 pups. Myc/ÎPOZ tumors [bvo002-bvo006] were obtained from Trp5Fl/Fl;Miz1ÎPOZ/POZ;Nestin-Cre cerebella of P6-P7 pups.

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.

Dataset Information

Elevated expression of the H3K36me2 demethylase Kdm8/Jmjd5, a direct Miz1 target gene causes prolonged postnatal Schwann cell proliferation in the murine Miz1∆POZ neuropathy

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