Genomic targets of the human c-Myc protein.

By P. Fernandez, S. Frank, Luquan Wang, M. Schroeder, Suxing Liu, J. Greene, A. Cocito, B. Amati. Genes & Development, 2003

1,044 citations recorded by the source corpus.

The transcription factor Myc is induced by mitogenic signals and regulates downstream cellular responses. If overexpressed, Myc promotes malignant transformation. Myc modulates expression of diverse genes in experimental systems, but few are proven direct targets. Here, we present a large-scale screen for genomic Myc-binding sites in live human cells. We used bioinformatics to select consensus DNA elements (CACGTG or E-boxes) situated in the 5' regulatory region of genes and measured Myc binding to those sequences in vivo by quantitative chromatin immunoprecipitation. Strikingly, most promoter-associated E-boxes showed selective recovery with Myc, unlike non-E-box promoters or E-boxes in bulk genomic DNA. Promoter E-boxes were distributed in two groups bound by Myc at distinct frequencies. The high-affinity group included an estimated 11% of all cellular loci, was highly conserved among different cells, and was bound independently of Myc expression levels. Overexpressed Myc associated at increased frequency with low-affinity targets and, at extreme levels, also with other sequences, suggesting that some binding was not sequence-specific. The strongest DNA-sequence parameter defining high-affinity targets was the location of E-boxes within CpG islands, correlating with an open, preacetylated state of chromatin. Myc further enhanced histone acetylation, with or without accompanying induction of mRNA expression. Our findings point to a high regulatory and biological diversity among Myc-target genes.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7502f8729cda0963bf7c65d5506241951ad3860c

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Citations in the corpus

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors (2008, background): “; and (iv) Myc targets: two sets of genes bound and activated by c-Myc, identified in two independent studie”
A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes (2006, background): “For instance, c-Myc and E2F1 are known to reciprocally activate transcription of one another, establishing a putative positive feedback circuit (Fernandez et al., 2003; Leone et al., 1997).”
ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context (2004, background): “9 × 10-23 by χ2 test) with respect to the expected 11% of background c-MYC targets among randomly selected genes [29].”
Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. (2006, background): “c-Myc protein may induce global histone acetylation (Fernandez et al., 2003), thus allowing Oct3/4 and Sox2 to bind to their specific target loci.”
MYC as a regulator of ribosome biogenesis and protein synthesis (2010, background): “MYC as a transcription factor Genome-wide location analyses and gene expression profiling have revealed that MYC binds to and potentially regulates the transcription of at least 15% of the genom”
MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. (2007, background): “The extent of target gene regulation by MYC-MAX transcription factor is dependent on the affinity for genomic binding sites and levels of the transcription factor (26).”
miR-24 inhibits cell proliferation by suppressing expression of E2F2, MYC and other cell cycle regulatory genes by binding to “seedless” 3′UTR microRNA recognition elements (2009, background): “, 2003) or may be mediated by MYC, given that MYC and E2F1 have been shown to transactivate each other (Fernandez et al., 2003).”
ChIP-seq guidelines and practices of the ENCODE and modENCODE consortia (2012, background): “not necessarily occupied at physiological levels (DeKoter and Singh 2000; Fernandez et al. 2003).”
MicroRNAs in cell proliferation, cell death, and tumorigenesis (2006, background): “Interestingly, E2F1 is known to be transcriptionally activated by c-Myc (Fernandez et al, 2003).”
Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis (2005, background): “Cytochrome c, HSP60, PHB, PRDX3, and mSHMT have been shown to be bound by Myc by ChIP assays (15, 31, 33, 36, 47).”
MYC on the Path to Cancer (2012, methodology): “Myc was documented by chromatin immunoprecipitation (ChIP) and quantitative PCR to bind a selected panel of promoters (Fernandez et al., 2003).”
Reverse engineering of regulatory networks in human B cells (2005, background): “8 × 10 −22 by χ 2 test) with respect to the expected 11% of MYC targets among randomly selected gene”
c-Myc and Cancer Metabolism (2012, neutral): “In addition, c-Myc has been shown to bind to the promoters of gene-encoding proteins involved in mitochondrial function (24, 67).”
Myc's broad reach. (2008, background): “Promoterproximal E-boxes within CpG-rich, H3-K4-methylated, euchromatic islands indeed appear to constitute conserved high-affinity Myc-binding sites in that Myc expressed at either endogenous or at higher levels can be found E-box-associated in several different cell lines (constituting ∼11% of all”