Key Points
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MYC is a key integrator of growth-regulatory and oncogenic signalling pathways.
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MYC binds open chromatin and functions as a transcriptional activator and repressor of selected gene subsets.
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Detection of MYC binding to chromatin should not be systematically equated to a productive transcriptional event.
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MYC regulates genes and pathways that can feed back on global RNA production.
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Various MYC target gene products are crucial for tumour maintenance and may be targeted therapeutically: identifying these key effectors is a main priority in the field.
Abstract
Two opposing models have been proposed to describe the function of the MYC oncoprotein in shaping cellular transcriptomes: one posits that MYC amplifies transcription at all active loci; the other that MYC differentially controls discrete sets of genes, the products of which affect global transcript levels. Here, we argue that differential gene regulation by MYC is the sole unifying model that is consistent with all available data. Among other effects, MYC endows cells with physiological and metabolic changes that have the potential to feed back on global RNA production, processing and turnover. The field is progressing steadily towards a full characterization of the MYC-regulated genes and pathways that mediate these biological effects and — by the same token — endow MYC with its pervasive oncogenic potential.
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Acknowledgements
The authors thank S. Campaner, E. Guccione, M. Morelli and G. Natoli for critical reading and comments. They apologize to colleagues whose work could not be cited owing to space constraints. Work in their laboratory is supported by grants from the European Community's Seventh Framework Programme (MODHEP consortium), the European Research Council, the Italian Health Ministry and the Italian Association for Cancer Research (AIRC) to B.A., and from Worldwide Cancer Research and the AIRC to A.S.
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Glossary
- SV40 viral antigens
-
The simian virus 40 (SV40) genome encodes two viral antigens, large T and small t, both of which are capable of transforming mammalian cells.
- Next-generation sequencing
-
(Also called high-throughput sequencing). Allows the parallel sequencing of millions of DNA molecules. This technology has facilitated the development of a series of techniques, such as the profiling of transcriptomes (RNA-sequencing) or of genome-wide protein–chromatin interactions (chromatin immunoprecipitation followed by sequencing).
- Chromatin immunoprecipitation
-
(ChIP). A technique in which DNA-associated proteins such as transcription factors, chromatin remodellers or histones are chemically crosslinked to DNA and then immunoprecipitated. The co-purified DNA can then be analysed by PCR (ChIP–PCR), hybridization (ChIP–chip) or next-generation sequencing (ChIP–seq).
- DNase I hypersensitive sites
-
Genomic regions that are particularly sensitive to DNase I-mediated cleavage. They are usually found in regions of open, less-packed chromatin and mark active or poised promoters and enhancers.
- Pioneer transcription factor
-
A transcription factor that can access closed heterochromatic regions of the genome and make them accessible for downstream chromatin remodellers and other transcription factors. Pioneer transcription factors are often involved in building the chromatin landscape to shape cell-type-specific transcription.
- Histone acetyltransferase
-
An enzyme that acetylates lysine residues in histone proteins and thereby has essential roles in proper gene activation and transcription.
- Tethering factors
-
Transcription factors or chromatin-associated proteins that recruit other proteins to target regions on DNA; tethering factors are not necessarily directly DNA-bound.
- RNA polymerase II carboxy-terminal domain
-
(Pol II CTD). Contains a series of heptad repeats (YSPTSPS or small variants, repeated 52 times in mammals) that are phosphorylated during the life cycle of Pol II-mediated transcription (initiation, pause release, elongation and termination) and regulate the various activities of Pol II.
- MYC–ER
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The MYC–ER fusion protein is a chimaera between the coding sequence of the human or mouse MYC mRNA and the hormone-binding domain of the oestrogen receptor (ER). A specific mutation in the ER domain makes MYC–ER activatable by synthetic 4-hydroxytamoxifen (4-OHT) but renders it insensitive to oestrogen.
- 4sU-labelling
-
4-thiouridine (4sU) is incorporated into actively transcribed RNA in live cells and can thus be used to study transcriptional regulation in vivo. RNA is extracted, and the labelled RNA is purified and subjected to genome-wide sequencing (4sU-seq).
- GRO–seq
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The genome-wide nuclear run-on (GRO) assay coupled with next-generation sequencing (–seq) is used to study elongation-competent RNA polymerase II on isolated nuclei by labelling and purifying short, nascent RNA fragments.
- Nearest-neighbour associations
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Promoters and enhancers form a complex interaction network that remains to be fully described in different physiological and cellular settings. If three-dimensional chromatin interaction maps are not available, nearest-neighbour associations link a given enhancer to its closest promoter, and vice versa.
- mRNA cap methylation
-
The 5′ cap of an mRNA consists of a guanine nucleotide that can be methylated by the enzyme RNA guanine-7 methyltransferase (RNMT). The 7-methylguanosine cap promotes several post-transcriptional events and is required for effective mRNA translation.
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Kress, T., Sabò, A. & Amati, B. MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer 15, 593–607 (2015). https://doi.org/10.1038/nrc3984
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DOI: https://doi.org/10.1038/nrc3984
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