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

Cole, Michael

doi:10.1101/cshperspect.a014316

Cited by 29 publications

(23 citation statements)

References 58 publications

(79 reference statements)

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“…Thus, besides interfering with the activating function of ZBTB17 or other transcription factors, MYC may repress transcription indirectly, owing to passive loss of RNAPII. MYC may also elicit repression through other indirect mechanisms, such as the induction of PTEN, resulting in augmented activity of the Polycomb Repressive Complex PRC2 (Kaur and Cole 2013;Cole 2014): this mechanism might not be relevant in our experiments, however, as PTEN was induced in none of the systems analyzed here.…”

Section: Discussionmentioning

confidence: 95%

Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation

et al. 2017

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Overexpression of the MYC transcription factor causes its widespread interaction with regulatory elements in the genome but leads to the up-and down-regulation of discrete sets of genes. The molecular determinants of these selective transcriptional responses remain elusive. Here, we present an integrated time-course analysis of transcription and mRNA dynamics following MYC activation in proliferating mouse fibroblasts, based on chromatin immunoprecipitation, metabolic labeling of newly synthesized RNA, extensive sequencing, and mathematical modeling. Transcriptional activation correlated with the highest increases in MYC binding at promoters. Repression followed a reciprocal scenario, with the lowest gains in MYC binding. Altogether, the relative abundance (henceforth, "share") of MYC at promoters was the strongest predictor of transcriptional responses in diverse cell types, predominating over MYC's association with the corepressor ZBTB17 (also known as MIZ1). MYC activation elicited immediate loading of RNA polymerase II (RNAPII) at activated promoters, followed by increases in pause-release, while repressed promoters showed opposite effects. Gains and losses in RNAPII loading were proportional to the changes in the MYC share, suggesting that repression by MYC may be partly indirect, owing to competition for limiting amounts of RNAPII. Secondary to the changes in RNAPII loading, the dynamics of elongation and pre-mRNA processing were also rapidly altered at MYC regulated genes, leading to the transient accumulation of partially or aberrantly processed mRNAs. Altogether, our results shed light on how overexpressed MYC alters the various phases of the RNAPII cycle and the resulting transcriptional response.[Supplemental material is available for this article.]The MYC transcription factor is overexpressed and acts as an oncogenic driver in numerous tumor types. Shedding light on the transcriptional programs driven by MYC is thus a critical area of investigation, with important translational implications. Indeed, numerous studies focused on the analysis of MYC-induced transcriptional responses, typically measuring its binding through ChIP-seq and profiling transcriptional maps by RNA-seq . A series of papers proposed that, rather than acting as a gene-specific regulator, MYC acts as a general amplifier of transcriptional activity (Lin et al. 2012;Nie et al. 2012). However, our re-analysis of the available data led us to reconsider this model and to conclude that the primary activity of MYC lies in the up-and down-regulation of selected sets of genes, RNA "amplification"-when occurring-being best explained as a secondary consequence (Sabò et al. 2014;Walz et al. 2014;Kress et al. 2015Kress et al. , 2016.At the mechanistic level, how MYC activates and represses transcription remains to be largely addressed. In particular, a unifying view on the role of MYC in the recruitment and progression of RNA polymerase II (RNAPII) within the transcriptional units of regulated genes and the consequent dynamics of transcriptiona...

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Section: Discussionmentioning

confidence: 95%

Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation

et al. 2017

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“…In fact, MYC represses many genes via the histone-lysine N-methyltransferase (EZH2)-induced genome trimethylation of H3K27. This occurs indirectly through MYC induction of the tumor suppressor PTEN, which then activates EZH2 via AKT phosphorylation in normal cells (Kaur and Cole 2013;Cole 2014). However, there is extensive evidence that MYC is directly recruited to non-E-box sequences at specific promoters through the interaction with other transcription factors, including MIZ-1, SP1/SP3, and NF-YB/NF-YC (Li et al 1994;Peukert et al 1997;Schneider et al 1997;Gartel et al 2001;Staller et al 2001).…”

Section: Cofactors Controlling Noncanonical Myc Transcriptional Activmentioning

confidence: 99%

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

Hann

2014

Cold Spring Harbor Perspectives in Medicine

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The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYC is overwhelming, there has been little consensus on the molecular functions of MYC that mediate its critical biological roles. In this perspective, the major MYC cofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type-and context-dependent fashion.

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“…These elements have been found to work as enhancers of transcription through their binding of transcription factors and the formation of chromatin loops that bring them in close proximity to target genes which can be nearby or distant. MYC is surrounded by a vast gene desert that contains several diseaseassociated SNPs that may map to potential regulator elements 27 . The effects of these regulatory elements cannot be fully captured by the usual exogenous reporter-based experiments.…”

Section: Discussionmentioning

confidence: 99%

A novel tool for monitoring endogenous human MYC transcription and translation by EGFP tag insertion at the 3’ end using CRISPR-Cas9 genome editing

Cumbal

Cole

2019

Preprint

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The MYC oncogene is overexpressed in over 70% of human cancers. Since its identification, the study of MYC has led to the discovery of the various ways through which oncogenes contribute to the ability of normal cells to become malignant. However, there are many aspects of MYC biology that remain unknown or controversial in terms of its regulation, targetability and downstream control of its targets. We developed two stable cell lines expressing MYC endogenously tagged with EGFP via CRISPR/Cas9-mediated genome editing. This system allows efficient detection of transcriptional activity of MYC as well the resulting fusion protein while maintaining the gene expression profiles, growth factors-associated MYC induction and growth kinetics of the parental cells. To our knowledge, this is the first report showing endogenous monitoring of MYC expression in colorectal adenocarcinoma through an EGFP tag, thus making it an efficient tool for high-throughput approaches such as genetic and drug screens.

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

Cited by 29 publications

References 58 publications

Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation

Integrative analysis of RNA polymerase II and transcriptional dynamics upon MYC activation

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

A novel tool for monitoring endogenous human MYC transcription and translation by EGFP tag insertion at the 3’ end using CRISPR-Cas9 genome editing

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