Evaluation of myc E-box phylogenetic footprints in glycolytic genes by chromatin immunoprecipitation assays
Open accessAbstract
Prediction of gene regulatory sequences using phylogenetic footprinting has advanced considerably but lacks experimental validation. Here, we report whether transcription factor binding sites predicted by dot plotting or web-based Trafac analysis could be validated by chromatin immunoprecipitation assays. MYC overexpression enhances glycolysis without hypoxia and hence may contribute to altered tumor metabolism. Because the full spectrum of glycolytic genes directly regulated by Myc is not known, we chose Myc as a model transcription factor to determine whether it binds target glycolytic genes that have conserved canonical Myc binding sites or E boxes (5'-CACGTG-3'). Conserved canonical E boxes in ENO1, HK2, and LDHA occur in 31- to 111-bp islands with high interspecies sequence identity (>65%). Trafac analysis revealed another region in ENO1 that corresponds to a murine region with a noncanonical E box. Myc bound all these conserved regions well in the human P493-6 B lymphocytes. We also determined whether Myc could bind nonconserved canonical E boxes found in the remaining human glycolytic genes. Myc bound PFKM, but it did not significantly bind GPI, PGK1, and PKM2. Binding to BPGM, PGAM2, and PKLR was not detected. Both GAPD and TPI1 do not have conserved E boxes but are induced and bound by Myc through regions with noncanonical E boxes. Our results indicate that Myc binds well to conserved canonical E boxes, but not nonconserved E boxes. However, the binding of Myc to unpredicted genomic regions with noncanonical E boxes reveals a limitation of phylogenetic footprinting. In aggregate, these observations indicate that Myc is an important regulator of glycolytic genes, suggesting that MYC plays a key role in a switch to glycolytic metabolism during cell proliferation or tumorigenesis.
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In human NPCs, both c-MYC and N-MYC bind to the HK2 and LDHA promoters in the region containing the E boxes.
“chromatin immunopreciptation with anti-c-MYC and N-MYC antibodies in human NPCs showed that both MYCs could bind to the HK2 and LDHA promoters in the region containing the E boxes as reported (Kim et al., 2004).”
From Metabolic reprogramming during neuronal differentiation from aerobic glycolysis to neuronal oxidative phosphorylation (2016) · cites this paper as Kim et al., 2004
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- Authors
- Kim, J.-W., Zeller, K. I., Wang, Y., Jegga, A. G., Aronow, B. J., O'Donnell, K. A., & Dang, C. V.
- Affiliations
- Graduate Program of Pathobiology
- Department of Medicine
- Graduate Program in Cellular and Molecular Medicine
- University of Cincinnati (US)
- Program in Human Genetics and Molecular Biology, The Johns Hopkins University School of Medicine
- Johns Hopkins University (US)
- Corresponding author
- Dang, Chi V.
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2004-07
- Volume
- 24
- Issue
- 13
- Pages
- 5923-5936
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC480875
- OpenAlex
- W2066807386
- Cited by
- 371
- References
- 47
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 21 · 2023: 26 · 2022: 28 · 2021: 28 · 2020: 22 · 2019: 17 · 2018: 22 · 2017: 19 · 2016: 15 · 2015: 15 · 2014: 17 · 2013: 14 · 2012: 14
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (T32HL007525)
- National Cancer Institute (CA 57341, R01CA057341, CA 51497, R37CA051497, R01CA051497)
- National Institute of General Medical Sciences (T32GM07819)
- U.S. National Library of Medicine (G13LM007515, LM07515)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- c-Myc, E-box, phylogenetic footprinting, transcription factor binding sites, glycolytic genes, chromatin immunoprecipitation, alpha-enolase, HK2, LDHA, cancer metabolism, glycolysis, gene expression regulation
- MeSH terms
- Base Sequence, Binding Sites, Chromatin, Glycolysis, Humans, Lymphocytes, Phylogeny, Precipitin Tests, Regulatory Sequences, Nucleic Acid, Transcription Factors, Proto-Oncogene Proteins c-myc, Conserved Sequence, DNA Footprinting, E-Box Elements, Cell Line, Tumor
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