Myc influences global chromatin structure

Knoepfler, Paul S.; Zhang, Xiao Yong; Cheng, Pei Feng; Gafken, Philip R.; McMahon, Steven B.; Eisenman, Robert N.

doi:10.1038/sj.emboj.7601152

Cited by 344 publications

(333 citation statements)

References 64 publications

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“…Consistent with the hypothesis that EZH2 activity controls global H3 methylation, we found that total cellular H3K27me3 levels were dramatically elevated by both MYC and EZH2/S21A expression (Kaur and Cole 2013). Previous studies showed that MYC can increase total cellular levels of the activating histone modifications, acetylated H3 and acetylated H4 (Knoepfler et al 2006), but this experiment showed a simultaneous increase in the repressive H3K27me3 modification. Because the EZH2/S21A mutant can completely recapitulate the effect of MYC on H3K27me3 levels, this is compelling evidence that MYC acts through reduced phosphorylation of EZH2.…”

Section: Ezh2 Activation Is Sufficient To Account For Myc-mediated Resupporting

confidence: 75%

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Cole

2014

Cold Spring Harbor Perspectives in Medicine

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MYC is one of the most frequently mutated and overexpressed genes in human cancer but the regulation of MYC expression and the ability of MYC protein to repress cellular genes (including itself ) have remained mysterious. Recent genome-wide association studies show that many genetic polymorphisms associated with disease risk map to distal regulatory elements that regulate the MYC promoter through large chromatin loops. Cancer risk-associated single-nucleotide polymorphisms (SNPs) contain more potent enhancer activity, promoting higher MYC levels and a greater risk of disease. The MYC promoter is also subject to complex regulatory circuits and limits its own expression by a feedback loop. A model for MYC autoregulation is discussed which involves a signaling pathway between the PTEN ( phosphatase and tensin homolog) tumor suppressor and repressive histone modifications laid down by the EZH2 methyltransferase.

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Section: Ezh2 Activation Is Sufficient To Account For Myc-mediated Resupporting

confidence: 75%

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Cole

2014

Cold Spring Harbor Perspectives in Medicine

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“…Intriguingly, we found that the percentage of H3 in this fraction is increased in both the Em-MYC pre-B and the lymphoma cells relative to wild-type cells. This suggests that a profound global change in chromatin solubility occurs upon overexpression of MYC, which is consistent with the global condensation that occurs with loss of N-MYC from neural progenitor cells (Knoepfler et al 2006). In addition, because the amount of soluble chromatin recovered from lymphoma cells increased relative to that from Em-MYC pre-B cells, increases in chromatin solubility are not simply consequences of MYC-driven cellular proliferation.…”

Section: Chromatin Solubility Increases During Myc-induced Oncogenesissupporting

confidence: 57%

Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis

Conerly¹,

Teves²,

Diolaiti³

et al. 2010

Genome Res.

118

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The histone variant H2A.Z has been implicated in the regulation of gene expression, and in plants antagonizes DNA methylation. Here, we ask whether a similar relationship exists in mammals, using a mouse B-cell lymphoma model, where chromatin states can be monitored during tumorigenesis. Using native chromatin immunoprecipitation with microarray hybridization (ChIP-chip), we found a progressive depletion of H2A.Z around transcriptional start sites (TSSs) during MYC-induced transformation of pre-B cells and, subsequently, during lymphomagenesis. In addition, we found that H2A.Z and DNA methylation are generally anticorrelated around TSSs in both wild-type and MYC-transformed cells, as expected for the opposite effects of these chromatin features on promoter competence. Depletion of H2A.Z over TSSs both in cells that are induced to proliferate and in cells that are developing into a tumor suggests that progressive loss of H2A.Z during tumorigenesis results from the advancing disease state. These changes were accompanied by increases in chromatin salt solubility. Surprisingly,~30% of all genes showed a redistribution of H2A.Z from around TSSs to bodies of active genes during the transition from MYC-transformed to tumor cells, with DNA methylation lost from gene bodies where H2A.Z levels increased. No such redistributions were observed during MYC-induced transformation of wild-type pre-B cells. The documented role of H2A.Z in regulating transcription suggests that 30% of genes have the potential to be aberrantly expressed during tumorigenesis. Our results imply that antagonism between H2A.Z deposition and DNA methylation is a conserved feature of eukaryotic genes, and that transcription-coupled H2A.Z changes may play a role in cancer initiation and progression.

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“…They regulate transcription by recruiting histone acetyltransferases (HAT) (McMahon et al 2000) and other chromatin-modifying factors (Eilers and Eisenman 2008). Changes in MYC levels have been shown to have widespread effects on chromatin marks (Knoepfler et al 2006). Importantly, MYC has also been shown to induce EZH2 expression in other cancers (Koh et al 2011;Salvatori et al 2011).…”

Section: Myc Proteins and The Epigenetic Landscape In Medulloblastomamentioning

confidence: 99%

Role of MYC in Medulloblastoma

Roussel

Robinson

2013

Cold Spring Harbor Perspectives in Medicine

130

109

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Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.

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Myc influences global chromatin structure

Cited by 344 publications

References 64 publications

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

MYC Association with Cancer Risk and a New Model of MYC-Mediated Repression

Changes in H2A.Z occupancy and DNA methylation during B-cell lymphomagenesis

Role of MYC in Medulloblastoma

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